Modulators of trpml, their compositions and methods of use

Abstract

The present disclosure relates to pharmaceutical compounds of the Formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable salt or composition thereof. Also provided are methods of use of TRPML modulators for treating disorders, the modulators including compounds of the Formula (I), (Ia), (Ib), or (Ic). Such methods of use include treatment of ciliopathies.

Description

[0001] MODULATORS OF TRPML, THEIR COMPOSITIONS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS The application claims the benefit of, and priority to, U.S.S.N.63 / 250,818, filed September 30, 2021; and U.S.S.N.63 / 339,791, filed May 9, 2022; the contents of each of which are incorporated herein by reference in their entirety. TECHNICAL FIELD The present disclosure relates to compounds and compositions which are modulators of TRPML and are useful for treatment of a variety of disorders. BACKGROUND The lysosome is a key organelle that serves as the cell's recycling center. In a highly regulated manner, it breaks down various biomaterials (proteins, lipids, and membranes) into smaller molecules or chemical building blocks, that the cell then employs for energy or as starting materials for new proteins or membranes [see e.g., de Duve, C., The lysosome turns fifty. Nat Cell Biol, 2005.7(9): p .847-9. Parkinson-Lawrence, E.J., et al., Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda), 2010.25(2): p .102-15]. Lysosomal dysfunction due to mutations in the hydrolytic enzyme of lysosomal transport occur in the more than 50 genetically defined Lysosomal Storage Diseases. Interestingly, defects in lysosomal processing can have substantial effects on the function of the organelle beyond the actual enzyme that is mutated – in effect, the system can be gummed up – altering lysosomal degradation and membrane transport / trafficking, creating a positive feedback loop. Because lysosome storage is also seen in common neurodegenerative diseases such as Alzheimer's and Parkinson's, understanding the mechanisms underlying the positive feedback loop may provide therapeutic approaches not only for LSDs, but also for common sporadic neurodegenerative diseases. A lysosome-localized cation channel, TRPML1, has been recently identified as a key regulator of lysosomal function and membrane trafficking processes in the lysosome. Human mutations of TRPML1 cause an inherited lysosomal storage disease, Mucolipidosis IV. This disease is typified by neurodegenerative effects likely driven by the accumulation of lipids and other biomaterials in the cell. The related channels TRPML2 and TRPML3 also regulate lysosomal function. Many reports suggest that TRPML channel activation is involved in multiple, key lysosomal functions. It can drive the translocation of the Transcription factor (TF)EB to the nucleus. TFEB regulates autophagy and lysosome biogenesis. Overexpression of TFEB has been reported to induce cellular clearance in several lysosome storage diseases, including Pompe Disease, Cystinosis, multiple sulfatase deficiency, as well as common neurodegenerative diseases, including Parkinson's disease and Huntington's disease (Settembre, C., et al., Signals from the lysosome: a control center for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol, 2013.14(5): p .283-96). Therefore, activation of TRPML channels by TRPML agonists may also lead to cellular clearance in all the aforementioned diseases, providing therapeutic targets for these devastating diseases. Recently, a potent synthetic agonist for TRPMLl has been reported [Shen, D., et al., Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun, 2012.3 : p .731]. This SF-51-related compound (Mucolipin Synthetic Agonist 1 or ML-SA1) that could induce significant [Ca2+] increases in HEK293 cells stably or transiently expressing TRPML1 protein that has been forced to the plasma membrane via deletion of its lysosomal targeting sequence. High concentrations of ML-SAl (~10 µΜ) are needed to effectively activate TRPMLs. Since that concentration is usually difficult to achieve in vivo, ML-SAl cannot be used to treat the above TRPML related diseases. Liang et al. recently reported a new class of compounds as more potent TRPML activators [WO 2018 / 005713A1]. These compounds were thought to be useful in treating disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, age-related common neurodegenerative diseases, ROS or oxidative stress related diseases, and aging. TRPML activators may also be useful in other disorders. SUMMARY OF THE DISCLOSURE The present disclosure provides for a compound of Formula (I) and subformulas thereof and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof. In an aspect, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein W1is N or CR5; W2is N or CR6; R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C1-6alkyl, C1-6alkoxy, -(CH2)1-2-cycloalkyl, -(CH2)1-2-heterocycloalkyl, or NRaRb, each R2optionally substituted by 1-5 independently selected R8; R3is each of R4, R5, and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; R9is C1-6alkyl or –(CH2)0-2-C3-7cycloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C1-3alkyl, and C1-6alkoxy, wherein C1-3alkyl and C1-6alkoxy are optionally substituted with 1-5 substituents independently selected from the group consisting of deuterium, hydroxyl, C1-3haloalkyl, C1-3alkoxy and C1-3alkyl; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, C(O)-C1-6alkyl, C(O)-C2-6alkenyl, –(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1 or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; wherein m + n is 2, 3, or 4; m1 + n1 is 0, 1, 2, 3, or 4; m2 + n2 is 0, 1, 2, 3, or 4; and R1and R2are not both aryl. In another aspect, provided is a compound of formula (Ib) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of formula (Ic) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of Formula (I), or any subformula thereof, selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating a disease or disorder that can be treated by modulation of TRPML, the method comprising administering to a patient in need thereof a compound described herein, or a composition described herein. Still other objects and advantages of the disclosure will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by the skilled artisan without departing from the spirit and scope of the disclosure. DETAILED DESCRIPTION OF THE DISCLOSURE As generally described herein, the present disclosure provides compounds (e.g., compounds of Formula (I), and its subformulas (Ia), (Ib), and (Ic), or compounds of Table 1, or pharmaceutically acceptable salts thereof) that are useful for disorders (e.g., polycystic kidney disease) associated with modulation of TRPML. “TRPML”, “TRPML ion channel” and “TRPML channel” are used interchangeably throughout. Compounds In an aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein W1is N or CR5; W2is N or CR6; R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, C1-6alkyl, C1-6alkoxy, -(CH2)1-2-cycloalkyl, -(CH2)1-2-heterocycloalkyl, or NRaRb, each R2optionally substituted by 1-5 independently selected R8; each of R4, R5, and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6 alkyl; R9is C1-6alkyl or –(CH2)0-2-C3-7cycloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C1-3alkyl, and C1-6alkoxy, wherein C1-3alkyl and C1-6alkoxy are optionally substituted with 1-5 substituents independently selected from the group consisting of deuterium, hydroxyl, C1-3haloalkyl, C1-3alkoxy and C1-3alkyl; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, , C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, C(O)-C1-6alkyl, C(O)-C2-6alkenyl,–(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1 or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; wherein m + n is 2, 3, or 4; m1 + n1 is 0, 1, 2, 3, or 4; m2 + n2 is 0, 1, 2, 3, or 4; and R1and R2are not both aryl. In some embodiments, W1is N. In some embodiments, W2is CR6. In some embodiments, W1is N and W2is CR6. In some embodiments, W1is CR5and W2is N. In some embodiments, W1is N and W2is N. In some embodiments, W1is CR5and W2is CR6. In some embodiments, the compound is of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-cycloalkyl, C1-6alkyl, C1-6alkoxy, or NRaRb, each R2optionally substituted by 1-5 independently selected R8; R3is each of R4and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6 alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6 haloalkyl, and C1-6 alkyl; each Raand Rbis independently selected from H, C1-6alkyl, , C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl, –(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; wherein m + n is 2, 3, or 4; and R1and R2are not both aryl. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl or C3-7cycloalkyl, optionally substituted by 1-5 independently selected R8; R3is each of R4and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,–(CH2)0-2-C3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and wherein m + n is 2, 3, or 4. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl, optionally substituted by 1-5 independently selected R8; R3is each of R4and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,–(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and wherein m + n is 2, 3, or 4. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl optionally substituted by 1-5 independently selected R8; R3is each of R4and R6is H; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7 cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,–(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1is pyridyl optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl optionally substituted by 1-5 independently selected R8; R3is each of R4and R6is H; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, and C1-6alkoxy; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl, and C1-6haloalkyl, each optionally substituted with 1-5 deuterium; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, R1is aryl optionally substituted by 1-5 independently selected R7. In some embodiments, R1is phenyl optionally substituted with 1-3 independently selected R7. In some embodiments, each R7is independently selected from H, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy. In some embodiments, R1is heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7. In some embodiments, R1is heteroaryl or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7. In some embodiments, R1is heteroaryl optionally substituted by 1-5 independently selected R7. In some embodiments, R1is monocyclic heteroaryl optionally substituted by 1-5 independently selected R7. In some embodiments, R1is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring heteroatoms selected from N only, wherein R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected R7. In some embodiments, R1is pyridine, thiazole, or pyrazole, optionally substituted by 1-4 independently selected R7. In some embodiments, R1is pyridine, optionally substituted by 1-4 independently selected R7. In some embodiments, R1is 2-pyridyl, optionally substituted by 1-4 independently selected R7. In some embodiments, R1is . In some embodiments, R1is , optionally substituted by 17 -4 independently selected R . In some embodiments, R1is heterocycloalkyl of 4-8 ring atoms, wherein 1-3 ring atoms are selected from N, O, and S, and R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is monocyclic heterocycloalkyl of 4-7 ring atoms, wherein 1-3 ring atoms are selected from N, O, and S, and R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is tetrahydropyran, azetidine, pyrrolidine, morpholine, or piperidine, and R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R1is C3-7cycloalkyl, optionally substituted by 1-4 independently selected R7. In some embodiments, R1is a cyclohexyl with an optional one or two carbon bridged ring, and R1is optionally substituted by 1-4 independently selected R7. In some embodiments, R2is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O- cycloalkyl, -O-heterocycloalkyl, C1-6alkoxy, C1-6alkyl, or NRaRb, each R2optionally substituted by 1-5 independently selected R8, and wherein Raand Rbof the R2group are not both H. In some embodiments, R2is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R2optionally substituted by 1-5 independently selected R8. In some embodiments, R2is aryl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is phenyl optionally substituted with 1-3 independently selected R8. In some embodiments, each R8is independently selected from H, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy. In some embodiments, R2is In some embodiments, R2is heteroaryl, cycloalkyl, or heterocycloalkyl, each R2optionally substituted by 1-5 independently selected R8. In some embodiments, R2is heteroaryl or heterocycloalkyl, each R2optionally substituted by 1-5 independently selected R8. In some embodiments, R2is heteroaryl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is monocyclic heteroaryl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R2is optionally substituted by 1-4 independently selected R8. In some embodiments, R2is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected R8. In some embodiments, R2is pyridine, pyrimidine, pyrazine, or pyrazole, optionally substituted by 1-4 independently selected R8. In some embodiments, R2is pyridine, optionally substituted by 1-4 independently selected R8. In some embodiments, R2is i In some embodiments, R2is wherein R2is not further substituted. In some embodiments, R2is In some embodiments, R2is cycloalkyl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is C3-8cycloalkyl optionally substituted with 1-5 independently selected R8. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with 1-3 independently selected R8. In some embodiments, R2is not substituted. In some embodiments, R2is cyclopropyl. In some embodiments, R2is heterocycloalkyl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is monocyclic heterocycloalkyl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is monocyclic heterocycloalkyl of 4-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R2is optionally substituted by 1-4 independently selected R8. In some embodiments, R2is azetidine, oxetane, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, or morpholine, optionally substituted by 1-4 independently selected R8. In some embodiments R2is azetidine, pyrrolidine, piperazine, or morpholine, optionally substituted by 1-4 independently selected R8. In some embodiments, R2contains a ring nitrogen atom and is bound to formula (I) at the ring nitrogen atom. In some embodiments, In some embodiments, R2is NRaRb, each R2optionally substituted by 1-5 independently selected R8, and wherein Raand Rbof the R2group are not both H. In some embodiments, Rais C1-6alkyl, and Rbis C1-6alkyl, C3-7cycloalkyl, or 3-7 membered heterocycloalkyl. In some embodiments, Raand Rbare each independently selected C1-6alkyl. In some embodiments, each R8is independently selected from deuterium, hydroxy, halogen, cyano, or C1-6alkoxy. In some embodiments, R2is C1-6alkyl optionally substituted by 1-5 independently selected R8. In some embodiments, R2is C1-6alkyl optionally substituted by 1-5 independently selected halogens. In some embodiments, R2is Me, Et, CHF2, or CF3. In some embodiments, R2is CHF2. In some embodiments, R2is CF3. In some embodiments, R2is not substituted. In some embodiments, R2is O-cycloalkyl, -O-heterocycloalkyl, or C1-6alkoxy, each R2optionally substituted by 1-5 independently selected R8. In some embodiments, R2is -O- C3-7cycloalkyl or C1-6alkoxy, each R2optionally substituted by 1-5 groups independently selected from alkyl and halogen. In some embodiments, R2is -O-C3-7cycloalkyl or C1-6alkoxy, each R2optionally substituted by 1-5 independently selected halogens. In some embodiments, R2is -O-cyclobutyl, -O-propyl, -O-methyl, -OCHF2, or -O-CF3. In some embodiments, m is 1 and n is 1. In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, each R10is independently selected from the group consisting of C1-6alkyl and C1-6haloalkyl, each optionally substituted with 1-5 deuteriums. In some embodiments, each R10is methyl. In some embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, R3is substituted with an edge fused or spiro fused cyclopropane; or R3includes a one or two carbon bridge or a single bond bridge; and R3is optionally additionally substituted by 1-4 R10. In some embodiments, R3is optionally additionally substituted by 1-4 R10. In some embodiments, R3is additionally substituted by 1-4 R10. In some embodiments, R3is In some embodiments, R3is not substituted by any additional R10. In some embodiments, R4is H. In some embodiments, R5is H. In some embodiments, R6is H. In some embodiments, R4and R6are H. In some embodiments, R4, R5, and R6are H. In some embodiments, each of R7and R8are independently selected at each occurrence from the group consisting of hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, and C3-7cycloalkyl, wherein each C1-6alkyl and C1-6alkoxy is optionally substituted with 1-3 halogens. In some embodiments, each R7is independently selected at each occurrence from the group consisting of halogen, cyano, C1-6alkyl, C1-6alkoxy, and CF3. In some embodiments, R9is C1-6alkyl optionally substituted with 1-5 halogens or 1-9 deuteriums. In some embodiments, R9is ethyl, isopropyl, or t-butyl; each optionally substituted with 1-5 halogens or 1-9 deuteriums. In some embodiments, R9is ethyl, isopropyl, or t-butyl. In some embodiments, R9is t-butyl. In some embodiments, R9is - C(CD3)3, -CH(CD3)2, or -CD2CD3. In some embodiments, R9is Me, Et, t-butyl, -C(CD3)3, -CH(CD3)2, -C(CD3)3, . In some embodiments, R9is Me, Et, t-butyl, -C(CD3)3, -CH(CD3)2, -C(CD3)3, isopropyl, In another aspect, provided is a compound of formula (Ib) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of formula (Ic) wherein the variable definitions are as described in the specification and claims. In another aspect, provided is a compound of Formula (I), or any subformula thereof, selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound achieves at least 50% of the maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for a TRPML and has an EC50less than 1 µM. In some embodiments, the compound achieves at least 50% of the maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for TRPML1 and has an EC50less than 1 µM. In some embodiments, the compound achieves a maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for TRPML1 which is at least 10 fold the maximal current achieved for any other TRPML. In another aspect pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the compounds disclosed in the specification or claims, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds CmpdNo.StructureN NNN 149 N N O O N NNN 150 N N O O F Cl N N N 151 N N N O O CmpdNo.StructureN N N N N 445 N N O O N N N N 446 N N O O NNN N N N F 447 N N O O

[0002] Cmpd No.StructureCN N NNN 604NCF3N O O F3C CN N NN605NN F F N H3C O O CN N NNN 606NCHF2N O O D3CCDCD3 3 Cmpd No.StructureCN NNN 616 N N O O CN N N NNN 617 N CF3N O O N CN N NNN 618 N CF3N O O Cmpd No.StructureNONNN 1004 N N O O F F NN1005NN NNN O O F F NN1006 N N F3C N Boc Deuterated Compounds In some embodiments, compounds described herein herein (e.g., a compound of Formula I, Ia, Ib, or Ic) are deuterium enriched. Deuterium (D or2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes1H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel over their non-enriched counterparts. The effects of deuterium modification on a compound’s metabolic properties are not predictable, even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated compound can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many compounds have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each compound. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term ”D” or “deuterium” indicates at least 45% incorporation of deuterium). The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance of D at the specified position in a compound of this invention and the naturally occurring abundance of that isotope. Increasing the amount of deuterium present in a compound herein (e.g., a compound of Formula I, Ia, Ib, or Ic) is called “deuterium-enrichment,” and such compounds are referred to as “deuterium-enriched” compounds. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound. In other embodiments, a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated at a potential site of deuteration on the compound of at least 3500 (52.5.% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be deuterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%). Because the natural abundance of deuterium is about 0.015%, a small percentage of naturally occurring compounds of herein (e.g., a compound of Formula I, Ia, Ib, or Ic) would be expected to have one naturally occurring compound with one deuterium present. In some embodiments, the compounds herein (e.g., a compound of Formula I, Ia, Ib, or Ic) comprise an amount of deuterium-enrichment that is more than the amount of deuterium-enrichment present in naturally occurring compounds herein (e.g., a compound of Formula I, Ia, Ib, or Ic) All percentages given for the amount of deuterium present are mole percentages. It can be difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials. Methods of Treatment Provided herein, in certain embodiments, is a method of modulating TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by modulation of TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by activation of TRPML ion channels, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. Provided herein, in certain embodiments, is a method of treating a disease or disorder that can be treated by activation of TRPML1, the method comprising administering to a patient in need thereof a compound described herein (e.g., a compound of Formula I, Ia, Ib, or Ic) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives thereof, or a composition described herein. In addition to compounds of Formula I, Ia, Ib, or Ic, modulators of the TRPML channels have been reported in several publications, including WO2018005713 and WO2018208630, which are incorporated herein in their entirety. In some embodiments, the TRPML ion channel is TRPML1. In some embodiments, the TRPML ion channel is TRPML2. In some embodiments, the TRPML ion channel is TRPML3. In some embodiments, the compound is a modulator of TRPML1. In some embodiments, the compound is a modulator of TRPML2. In some embodiments, the compound is a modulator of TRPML3. In some embodiments, modulation of the TRPML ion channel comprises activation of the ion channel. In some embodiments, the disease or disorder is a ciliopathy (e.g., polycystic kidney disease). Exemplary ciliopathies include, but not limited to, polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In an aspect, provided is a method of treating a disorder which can be treated by modulation of lysosomes, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure. In an aspect, provided is a method of treating a disorder selected from the group consisting of a ciliopathy, neurodegenerative disease, lysosomal storage disorder, lysosomal transport disorder, glycogen storage disorder, cholesteryl ester storage disease, a muscular disease (e.g., muscular dystrophy), a disease related to aging (e.g., photo aging of the skin), macular degeneration (e.g., Stargardt’s or age-related), and cancer (e.g., cancers of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testes, colon, pancreas, or skin), the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the disclosure or a compound of the disclosure. In some embodiments, the disorder is a ciliopathy. In some embodiments, the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In some embodiments, the disorder is polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the disorder is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, GBA-Parkinson’s disease, LRRK2 Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewy body dementia, Pick’s disease, and multi system atrophy. In some embodiments, the disorder is a lysosomal storage disorder. In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, neuronopathic Gaucher’s disease, sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, gangliosidoses, Gaucher Disease, Lysosomal acid lipase deficiency, sulfatidoses, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses. In some embodiments, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay- Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie sundrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, pseudo-Hurler polydystrophy, phosphotransferease deficiency, mucolipidin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipfuscinosis, late infantile variant neuronal ceroid lipfuscinosis, type 7 neuronal ceroid lipfuscinosis, northern epilepsy neuronal ceroid lipfuscinosis, Turkish late infantile neuronal ceroid lipfuscinosis, German / Serbian late infantile neuronal ceroid lipfuscinosis, congential cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylgluosaminuria, and fucosidosis. In some embodiments, the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, and neuronopathic Gaucher’s disease. In some embodiments, the disorder is a lysosomal transport disease selected from the group consisting of cystinosis, pycnodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease. In some embodiments, the disorder is a glycogen storage disease selected from the group consisting of Pompe disease and Danon disease. In an aspect, provided is a method of treating a ciliopathy disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound capable of modulating TRPML, or a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In some embodiments, the compound is selected from the compounds disclosed in the specification. In some embodiments, the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Meckel-Gruber Syndrome, oral-facial- digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In some embodiments, the disorder is polycystic kidney disease In some embodiments, the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease. In some embodiments, the disorder is autosomal dominant polycystic kidney disease. In some embodiments, the method further comprises the use of a second therapeutic agent. In some embodiments, the method is to treat a ciliopathy. In some embodiments, the second therapeutic agent is selected from the group consisting of an mTOR inhibitor, V2 receptor antagonist, tyrosine kinase inhibitor, somatostatin analog, glucosylceramide synthase inhibitor, microRNA-17 inhibitor, siRNA against p53, KEAP1-Nrf2 activator, xanthine oxidase inhibitor, PPARγ agonist, metformin, and beta hydroxybutyrate. In some embodiments, the second therapeutic agent is selected from the group consisting of tolvaptan, lixivaptan, mozavaptan, satavaptan, sirolimus, tacrolimus, everolimus, bosutinib, tesavatinib, imatinib, gefitinib, erlotinib, dasatinib, octreotide, pasireotide, venglustat, eliglustat, miglustat, microRNA-17 inhibitor, bardoxolone methyl, allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and beta hydroxybutyrate. In some embodiments, the second agent is tolvaptan. In some embodiments, the second therapeutic agent is selected from the group consisting of an immunomodulator, a calcineurin inhibitor, a renin angiotensin aldosterone system inhibitor, an antiproliferative agent, an alkylating agent, a corticosteroid, an angiotensin converting enzyme inhibitor, an adrenocorticotropic hormone stimulant, an angiotensin receptor blocker, a sodium- glucose transport protein 2 inhibitor, a dual sodium- glucose transport protein 1 / 2 inhibitor, a nuclear Factor- 1 (erythroid-derived 2)-like 2 agonist, a chemokine receptor 2 inhibitor, a chemokine receptor 5 inhibitor, an endothelin 1 receptor antagonist, a beta blocker, a mineralocorticoid receptor antagonist, a loop or thiazide diuretic, a calcium channel blocker, a statin, a short- intermediate or long-acting insulin, a dipeptidyl peptidase 4 inhibitor, a glucagon-like peptide 1 receptor agonist, a sulfonylurea, an apoptosis signal-regulating kinase- 1, a chymase inhibitor, a selective gly cation inhibitor, a renin inhibitor, an interleukin-33 inhibitor, a farnesoid X receptor agonist, a soluble guanylate cyclase stimulator, a thromboxane receptor antagonist, a xanthine oxidase inhibitor, an erythropoietin receptor agonist, a cannabinoid receptor type 1 inverse agonist, a NADPH oxidase inhibitor, an anti-vascular endothelial growth factor B, an anti-fibrotic agent, a neprilysin inhibitor, a dual CD80 / CD86 inhibitor, a CD40 antagonist, a cellular cholesterol and lipid blocker, a PDGFR antagonist, a Slit guidance ligand 2, an APOLl inhibitor, an Nrl2 activator / NF-kB inhibitor, a somatostatin receptor agonist, a PPAR gamma agonist, a AMP activated protein kinase stimulator, a tyrosine kinase inhibitor, a glucosylceramide synthase inhibitor, an arginine vasopressin receptor 2 antagonist, a xanthine oxidase inhibitor, a vasopressin receptor 2 antagonist, anti-amyloid beta antibodies, anti-Tau antibodies, anti- synuclein antibodies, dopamine precursors (e.g. L-DOPA), dopamine agonists (e.g. bromocriptine, cabergoline, pergolide, pramipexole and apomorphine), MAO-B inhibitors (e.g. rasagiline and selegiline), anticholinergics (e.g. orphenadrine, procyclidine and trihexyphenidyl), enhancers of b-glucocerebrosidase activity (e.g. ambroxol and afegostat), amantadine, and agents capable of treating Alzheimer’s (e.g., acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, and NMDA receptor antagonists such as memantine). In some embodiments, the second therapeutic agent is selected from the group consisting of COX inhibitors including arylcarboxylic acids (salicylic acid, acetylsalicylic acid, diflunisal, choline magnesium trisalicylate, salicylate, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid and triflumic acid), arylalkanoic acids (diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin and sulindac) and enolic acids (phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, and isoxicam; treatments for pulmonary hypertension including prostanoids (epoprostenol, iloprost, and treprostinil), endothelin receptor antagonists (bosentan, ambrisentan, and macitentan), phosphodiesterase-5 inhibitors (sildenafil and tadalafil), and sGC stimulators (riociguat); rho-kinase inhibitors, such as Y-27632, fasudil, and H-1152P; epoprostenol derivatives, such as prostacyclin, treprostinil, beraprost, and iloprost; serotonin blockers, such as sarpogrelate; endothelin receptor antagonists, such as besentan, sitaxsentan, ambrisentan, and TBC3711; PDE inhibitors, such as sildenafil, tadalafil, udenafil, and vardenafil; soluble gunaylate cyclase inhibtors such as riociguat and vericiguat; calcium channel blockers, such as amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, and perhexiline; tyrosine kinase inhibitors, such as imatinib; inhaled nitric oxide and nitric oxide- donating agents, such as inhaled nitrite; ΙκΒ inhibitors, such as IMD 1041 ; prostacyclin receptor agonists, such as selexipag; stimulators of hematopoiesis, such as TXA 127 (angiotensin (1-7)), darbepoetin alfa, erythropoetin, and epoetin alfa; anticoagulants and platelet-inhibiting agents; and diuretics; dietary and nutritional supplements such as acetyl- L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, vitamin C, L-dopa; immunosuppressants (for transplants and autoimmune-related RKD); anti-hypertensive drugs (for high blood pressure-related RKD, e.g., angiotensin-converting enzyme inhibitors and angiotensin receptor blockers); insulin (for diabetic RKD); lipid / cholesterol-lowering agents (e.g., HMG- CoA reductase inhibitors such as atorvastatin or simvastatin); and treatments for hyperphosphatemia or hyperparathyroidism associated with CKD (e.g., sevelamer acetate, cinacalcet). The present disclosure further provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present disclosure further provides methods of modulating TRPML in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating a disease or disorder in a subject, the method comprising: (a) detecting a disease or disorder associated with TRPML; and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, exemplary compounds of Formula (I) or (II) include the compounds described in Table 1 and in the Examples, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof. Accordingly, the present disclosure provides compounds useful for treating ciliopathies and related diseases. Compounds that modulate TRPML channels may be useful in the prophylaxis and treatment of any of the foregoing injuries, diseases, disorders, or conditions. In addition to in vitro assays of the activity of these compounds, their efficacy can be readily tested in one or more animal models. This disclosure is not limited in its application to the details of the methods and compositions described herein. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. Pharmaceutical Compositions and Routes of Administration The present disclosure provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Also provided herein are methods of modulating TRPML channels in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, pharmaceutical compositions containing compounds described herein such as a compound of Formula I, Ia, Ib, or Ic, or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a ciliopathy. The amount and concentration of compounds of Formula I, Ia, Ib, or Ic in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable diluents, excipients or carriers. The compounds according to the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting. Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art. Thus, another aspect of the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) transmucosally; (9) nasally; or (10) intrathecally. Additionally, compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present disclosure, which is effective for producing some desired therapeutic effect, e.g., by modulating EHMT1 or EHMT2, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment. The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug, or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Formulations of the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent. Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. A compound of the present disclosure may also be administered as a bolus, electuary or paste. In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. Liquid dosage forms for oral administration of the compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the heart, lung, bladder, urethra, ureter, rectum, or intestine. Furthermore, compositions can be formulated for delivery via a dialysis port. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion. In some embodiments, the compositions are administered by intravenous infusion or injection. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise one or more compounds of the disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. When the compounds of the present disclosure are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The addition of the active compound of the disclosure to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977). Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site. Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections. In addition, the methods described herein can be used to treat domesticated animals and / or pets. A subject can be male or female. A subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment. Dosages Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The compound and the pharmaceutically active agent can be administrated to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times). When administrated at different times, the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4, hours, 8 hours, 12 hours, 24 hours of administration of the other agent. When the compound and the pharmaceutically active agent are administered in different pharmaceutical compositions, routes of administration can be different. The amount of compound that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1% to 99% of compound, preferably from about 5% to about 70%, most preferably from 10% to about 30%. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferred. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the EC50(i.e., the concentration of the therapeutic which achieves a half- maximal effect) as determined in cell culture. Levels in plasma may be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment or make other alteration to treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the drugs. The desired dose can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule. Such sub-doses can be administered as unit dosage forms. In some embodiments, administration is chronic, e.g., one or more doses daily over a period of weeks or months. Examples of dosing schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more. The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated. Selected Chemical Definitions At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. In case a compound of the present disclosure is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk or wavy line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom, usually a carbon, oxygen, or nitrogen atom, is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto or oxo (i.e. , then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g. , C=C, C=N, N=N, etc.). As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C1-4alkyl is intended to include C1, C2, C3, and C4. C1-6alkyl is intended to include C1C2, C3, C4, C5, and C6alkyl groups and C1-8alkyl is intended to include C1, C2, C3, C4, C5, C6, C7, and C8. Some examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n- hexyl, n-heptyl, and n-octyl. As used herein, "alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bond that can occur in any stable point along the chain, such as ethenyl and propenyl. For example, C2-6alkenyl is intended to include C2, C3, C4, C5, and C6alkenyl groups and C2-8alkenyl is intended to include C2, C3, C4, C5, C6, C7, and C8alkenyl groups. As used herein, "alkylene" is intended to include moieties which are diradicals, i.e. , having two points of attachment. A non-limiting example of such an alkylene moiety that is a diradical is -CH2CH2-, i.e., a C2alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule. The alkylene diradicals are also known as "alkylenyl" radicals. Alkylene groups can be saturated or unsaturated (e.g., containing - CH=CH- or -C≡C- subunits), at one or several positions. In some embodiments, alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms). Some examples of alkylene groups include, but are not limited to, methylene, ethylene, n- propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert- butylene, n- pentylene, iso-pentylene, sec-pentylene and neo-pentylene. As used herein, "cycloalkyl" is intended to include saturated or unsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, the term "C3-8cycloalkyl" is intended to include C3, C4, C5, C6, C7, and C8cycloalkyl groups. Cycloalkyls may include multiple spiro- or fused or bridged rings. For example, cycloalkyl can include, but is not limited to, spiro butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, bicyclo butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl groups, adamantyl groups, and norbornyl groups. As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, or Se), unless specified otherwise. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4- dioxa-8-azaspiro[4.5]decanyl and the like. As used herein, "amine" or "amino" refers to unsubstituted - H2unless otherwise specified. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo substituents. As used herein, "haloalkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogen (for example -CvFwH2v.w+1wherein v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkoxy groups include, but are not limited to, tnfluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. As used herein, "alkoxyl" or "alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-6alkoxy, is intended to include C1, C2, C3, C4, C5, and C6alkoxy groups. C1-8alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, and C8alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, s-pentoxy, n-heptoxy, and n- octoxy. As used herein, "aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Aryl may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. As used herein, the terms "aromatic heterocycle," "aromatic heterocyclic" or "heteroaryl" ring are intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycle or heteroaryl rings, only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or R wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)P, wherein p = 1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of aromatic heterocycles, aromatic heterocyclics or heteroaryls include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly, carbazolyl, 4aH- carbazolyl, carbolinyl, cinnolinyl, furazanyl, imidazolyl, imidazolonyl, lH-indazolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl, methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5- thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH3-CH(OH)-. The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N. As used herein, "oxo" is means a "C=O" group. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds or tautomers thereof, or salts thereof, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds or tautomers thereof, wherein the parent compound or a tautomer thereof, is modified by making of the acid or base salts thereof of the parent compound or a tautomer thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, or a tautomer thereof, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound or a tautomer thereof that contains a basic or acidic moiety by conventional chemical methods. Generally, such pharmaceutically acceptable salts can be prepared by reacting the free acid or base forms of these compounds or tautomers thereof with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.1445 (1990). As used herein, "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. As used herein, the term "treating" refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing, or preventing the further development of a disorder, and / or reducing the severity of symptoms that will or are expected to develop. As used herein, "unsaturated" refers to compounds having at least one degree of unsaturation (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds. As used herein, the term "effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt of the compound or tautomer (including combinations of compounds and / or tautomers thereof, and / or pharmaceutically acceptable salts of said compound or tautomer) of the present disclosure that is effective when administered alone or in combination as an antimicrobial agent. For example, an effective amount refers to an amount of the compound or tautomer thereof, or a pharmaceutically acceptable salt said compound or tautomer that is present in a composition, a formulation given to a recipient patient or subject sufficient to elicit biological activity. In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification will control. As used herein, "mammal" refers to human and non-human patients. As used herein, the term "formulae of the disclosure" or "formulae disclosed herein" includes one or more of the Formulas I, its subformulas Ia, Ib, or Ic, and further subformulas thereof. As used herein, the term "compound of the disclosure" or "compound disclosed herein" includes one or more compounds of the formulae of the disclosure or a compound explicitly disclosed herein. All percentages and ratios used herein, unless otherwise indicated, are by weight. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present disclosure also consist essentially of, or consist of, the recited components, and that the processes of the present disclosure also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously. Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to modulate TRPML), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound. In general, the compounds of the present disclosure may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known but are not mentioned here. As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. The term, “treat” or “treatment,” as used herein, refers to the application or administration of a compound, alone or in combination with, an additional agent to a subject, e.g., a subject who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder. As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human subject having a disorder, e.g., a disorder described herein. The term “non-human animals” of the disclosure includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc. The terms “antagonist” and “inhibitor” are used interchangeably to refer to an agent that decreases or suppresses a biological activity. The terms “activator” and “agonist” are used interchangeably to refer to an agent that increases or initiates a biological activity. The term "hydrate" as used herein, refers to a compound formed by the union of water with the parent compound. The term “preventing,” when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount. Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and / or delaying the onset of symptoms of the infection in a treated population versus an untreated control population. Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population. The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of the solute).Another aspect of the disclosure features a pharmaceutical preparation suitable for use in a human patient, or for veterinary use, comprising an effective amount of a compound of the formulae of the disclosure (or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt), and one or more pharmaceutically acceptable excipients. The disclosure further contemplates the use of compounds of the formulae of the disclosure in the manufacture of a medicament or pharmaceutical preparation to treat or reduce the symptoms of any of the diseases or conditions provided in the specification. The compounds of the formulae of the disclosure for use in treating a particular disease or condition can be formulated for administration via a route appropriate for the particular disease or condition. Compounds of the formulae of the disclosure can be administered alone or in combination with another therapeutic agent. For instance, the compounds of the formulae of the disclosure can be administered conjointly with one or more of an agent for treating polycystic kidney disease, etc. Compounds of the formulae of the disclosure can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly, intraspinally, intrasternally, sublingually, or by inhalation. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered topically. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered orally. In some embodiments, compounds of Formula I, Ia, Ib, or Ic can be administered parentally. Compounds of Formula I, Ia, Ib, or Ic include molecules having an aqueous solubility suitable for oral or parenteral (e.g., intravenous) administration leading to or resulting in the treatment of a disorder described herein, for example the treatment of pain. In some embodiments, the compound is formulated into a composition suitable for oral administration. In some embodiments, a compound of Formula I, Ia, Ib, or Ic can be administered as part of an oral or parenteral (e.g., intravenous) pharmaceutical composition to treat a disorder described herein in a therapeutically effective manner. Certain compounds disclosed herein may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. For example, if one chiral center is present in a molecule, the disclosure includes racemic mixtures, enantiomerically enriched mixtures, and substantially enantiomerically or diastereomerically pure compounds. The composition can contain, e.g., more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a single enantiomer or diastereomer. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. The “enantiomeric excess” or “% enantiomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee = (90-10) / 100 = 80%. Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. The “diastereomeric excess” or “% diastereomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one diastereomer, and 10% of another enantiomer. de = (90-10) / 100 = 80%. Thus, a composition containing 90% of one diastereomer and 10% of the other diastereomer is said to have a diastereomeric excess of 80%. Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. EXAMPLES Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results. General. All oxygen and / or moisture sensitive reactions were carried out under N2atmosphere in glassware that was flame-dried under vacuum (0.5 mmHg) and purged with N2prior to use. All reagents and solvents were purchased from commercial vendors and used as received or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz1H, 75 MHz13C) or Varian (400 MHz1H, 75 MHz13C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, t = triplet, q = quartet, m = multiplet; coupling constant(s) in Hz). Unless otherwise indicated NMR data were collected at 25oC. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromatography / Mass Spectrometry (LCMS) was performed on Agilent 1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO4) stain followed by heating. LCMS typical conditions: LC-MS conditions Instrument : LCMS2020(E-LCMS 008) Column : Shim-pack GIST C18 ,50*4.6mm 5um Mobile Phase : A: H2O(0.1%FA) B: CH3CN Temperature : 35¡æ Flow rate : 2.5mL / min Run time : 0.1min@20%B,1.7min gradient(20-95% B), then0.7min@95% B,then0.4min@20% B Injection volume : 5 uL Detector : UV 220 / 254nm Mass range : 100- 1000 Scan : Postive / Negative. HPLC Typical Conditions: Instrument : LC-20AD(E-LC 006) Column : YMC Triart C18, 50×4.6 mm,5um Mobile phase : Solvent A: H2O / CH3CN / TFA=90 / 10 / 0.1 Solvent B: H2O / CH3CN / TFA=10 / 90 / 0.1 Flow rate : 2.5mL / min Run time : 0.4 min@ 60% B, 3.4min gradient (60-100% B), then 0.8min@100%B. Temperature : 35°C Detector : UV. Or Instrument : LC-2010AHT(E-LC 001) Column : Gemini, C18 , 50×4.6 mm,5um Mobile phase : Solvent A: H2O / CH3CN / TFA=90 / 10 / 0.1 Solvent B: H2O / CH3CN / TFA=10 / 90 / 0.1 Flow rate : 2.5mL / min Run time : 0.4 min@ 20% B, 3.4min gradient (20-95% B), then 0.8min@95%B. Temperature : 40 ℃. Detector : UV. Table 2: Abbreviations

[0003] Example 1. Synthesis of tert-butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 146) Compound 146Step 1. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1- carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol, prepared following the procedure outlined in compound 134 in EtOH (50 mL) was added tert-butyl piperazine-1-carboxylate (1.7 g, 9.2 mmol) and DIPEA (5.0 mL, 28 mmol). The resulting mixture was heated to 100oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5- iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1-carboxylate (4.5 g, 83%) as a white solid. LC / MS ESI (m / z): 584 (M+H)+. Step 2. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1-carboxylate (2.0 g, 3.4 mmol) in toluene (50 mL) were added cyclopropylboronic acid (0.35 g, 4.1 mmol), K2CO3(9.5 g, 69 mmol) and Pd-118 (0.22 g, 0.34 mmol). The resulting mixture was heated to 80oC overnight. After being cooled down to room temperature, the solvent was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (1.3 g, 76%) as a white solid. LC / MS ESI (m / z): 498 (M+H)+. Step 3. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1- carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperazine-1-carboxylate (1.3 g, 2.6 mmol) in THF (10 mL) was added TBAF (16 mL, 16 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (810 mg, 90%) as a white solid. LC / MS ESI (m / z): 344 (M+H)+. Step 4. tert-Butyl 4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl) piperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7H-pyrrolo [2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (100 mg, 0.29 mmol) in DMF (5 mL) were added 1,3-difluoro-5- iodobenzene (84 mg, 0.35 mmol), trans-cyclohexane-1,2-diamine (9.9 mg, 0.087 mmol), CuI (17 mg, 0.087 mmol) and K3PO4(190 mg, 0.87 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4-(5-cyclopropyl-7-(3,5- difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (82 mg, 62%) as a white solid. LC / MS ESI (m / z): 456 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.38 – 7.33 (m, 2H), 6.91 (d, J = 0.8 Hz, 1H), 6.79 – 6.72 (m, 1H), 3.69 (d, J = 2.7 Hz, 4H), 3.65 – 3.59 (m, 4H), 2.08 – 2.01 (m, 1H), 1.50 (s, 9H), 1.07 – 1.00 (m, 2H), 0.80 – 0.73 (m, 2H). The following compounds were prepared using a procedure analogous to the synthesis of compound 146 from the corresponding aryl halides, boronic esters or acids and amines. For analogs 474 and 475, trifluoro(oxetan-3-yl)-λ4-borane (potassium salt) was used in the coupling step. In case of analogs 465, 466, 467, 468, 469, and 470, the final product was obtained by hydrogenation, similar to Example 69, in the last step. Example 2. Synthesis of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 134) Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (1.0 g, 27 mmol, 60% wt%) in anhydrous DMF (60 mL) at 0oC was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in portions. The resulting mixture was stirred at the same temperature for 30 minutes before TsCl (3.4 g, 18 mmol) was added in portions. After addition, the reaction was stirred at room temperature overnight. The reaction was poured into ice water, filtered, the solid was collected and further dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 77%) as a white solid. LCMS ESI (m / z): 434 (M+H)+. Step 2. tert-Butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol) in DIPEA (5.0 mL, 28 mmol) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1- carboxylate (2.0 g, 9.2 mmol). The resulting mixture was heated to 150oC for 3 h under N2. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (2.5 g, 43%) as a yellow solid. LC / MS ESI (m / z): 612 (M+H)+. Step 3. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (2.5 g, 4.0 mmol) in dioxane (30 mL) and H2O (6 mL) were added (2-fluorophenyl)boronic acid (0.68 g, 4.8 mmol), K2CO3(1.7 g, 12 mmol) and Pd(dppf)Cl2(0.29 g, 0.40 mmol). The resulting mixture was stirred at 80oC overnight under N2. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.9 g, 82%) as a yellow solid. LC / MS ESI (m / z): 580 (M+H)+. Step 4. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.9 g, 3.3 mmol) in THF (20 mL) was added TBAF (20 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.2 g, 85%) as a white solid. LC / MS ESI (m / z): 426 (M+H)+. Step 5. tert-Butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.47 mmol) in DMF (10 mL) were added 2-bromopyridine (0.05 mL, 0.56 mmol), trans-cyclohexane-1,2-diamine (16 mg, 0.14 mmol), CuI (27 mg, 0.14 mmol) and K3PO4(300 mg, 1.4 mmol). The resulting mixture was heated to 100oC overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, the organic layer was separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (110 mg, 47%) as a white solid, 30 mg of which was further purified by prep-HPLC to afford 13 mg of white solid. LC / MS ESI (m / z): 503 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 – 8.48 (m, 1H), 8.26 (s, 1H), 7.93 – 7.87 (m, 1H), 7.50 (td, J = 7.5, 1.6 Hz, 1H), 7.39 – 7.33 (m, 1H), 7.25 – 7.17 (m, 3H), 4.30 – 4.04 (m, 2H), 3.39 – 3.22 (m, 3H), 2.92 – 2.70 (m, 1H), 1.43 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). The following compounds were prepared by the procedure analogous to the synthesis of compound 134 from the corresponding aryl halides. Example 3. Synthesis of ethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 137) Compound 137Step 1.4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(pyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (80 mg, 0.16 mmol) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 4h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO3(aq.), and the organic layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine which was carried directly to the next step. LC / MS ESI (m / z): 403 (M+H)+. Step 2. Ethyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl) -7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate To a 0oC solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5- (2-fluorophenyl)-7- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.15 mmol) in DCM (3 mL) was added TEA (0.062 mL, 0.45 mmol), followed by ethyl chloroformate (0.03 mL, 0.29 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice and the combined organic layers were washed with NaHCO3(aq.), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford ethyl (2R,5S)-4- (5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (39 mg, 54%) as a white solid. LC / MS ESI (m / z): 475 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 – 8.48 (m, 1H), 8.26 (s, 1H), 7.93 – 7.87 (m, 1H), 7.50 (td, J = 7.5, 1.6 Hz, 1H), 7.40 – 7.31 (m, 1H), 7.25 – 7.15 (m, 3H), 4.37 – 4.04 (m, 4H), 3.43 – 3.22 (m, 3H), 2.95 – 2.71 (m, 1H), 1.23 (t, J = 6.5 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). The following compounds were prepared using a procedure analogous to the synthesis of compound 137 from the corresponding aryl halides. Example 4. Synthesis of tert-butyl 4-(7-(5-chloro-2-methylphenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 159) Compound 159Step 1. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 6.9 mmol, prepared following the procedure outlined in compound 134, step 1) and tert-butyl 3- methylpiperazine-1-carboxylate (5.6 g, 28 mmol) was heated to 150oC for 3 h. After being cooled down to room temperature, the reaction was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2.0 g, 48%) as a white solid. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl 3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate (2.0 g, 3.3 mmol) in dioxane (30 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.9 mL, 13 mmol), TEA (2.3 mL, 17 mmol), X-Phos (0.16 g, 0.33 mmol) and Pd2(dba)3(0.31 g, 0.33 mmol ). The resulting mixture was stirred at 95oC overnight. After being cooled down to room temperature, the reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford tert-butyl 3-methyl-4-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate as a yellow solid which was used in the next step directly. LC / MS ESI (m / z): 598 (M+H)+. Step 3. tert-Butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d] pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (700 mg, 1.1 mmol) in dioxane (10 mL) and H2O (2 mL) were added 2-bromopyridine (0.22 mL, 2.3 mmol), K2CO3(810 mg, 5.8 mmol) and Pd(dppf)Cl2(86 mg, 0.11 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (490 mg, 76%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 4. tert-Butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d] pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (490 mg, 0.89 mmol) in THF (5 mL) was added TBAF (5.4 mL, 5.3 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 56%) as a white solid. LC / MS ESI (m / z): 395 (M+H)+. Step 5. tert-Butyl 4-(7-(5-chloro-2-methylphenyl)-5-(pyridin-2-yl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol) in DCM (10 mL) were added (5-chloro- 2-methylphenyl)boronic acid (130 mg, 0.76 mmol), Cu(OAc)2(180 mg, 1.0 mmol), pyridine (0.12 mL, 1.5 mmol) and 4A molecular sieves (400 mg). The resulting mixture was heated to 40oC for 3 days under an O2atmosphere. After being cooled down to room temperature, the reaction was quenched with NH4OH, diluted with DCM, and then filtered. The filtrate was extracted with DCM twice and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to give the product which was further purified by prep-HPLC to afford tert-butyl 4-(7-(5-chloro-2- methylphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (30 mg, 22%) as a yellow solid. LC / MS ESI (m / z): 519 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.70 – 8.65 (m, 1H), 8.47 (s, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.39 – 7.31 (m, 3H), 7.26 – 7.23 (m, 1H), 4.48 – 4.19 (m, 1H), 3.96 – 3.78 (m, 1H), 3.68 – 3.48 (m, 2H), 3.23 – 2.72 (m, 3H), 2.11 (s, 3H), 1.44 (s, 9H), 1.07 (s, 3H). The following compounds were prepared using a procedure analogous to the synthesis of compound 159 from the corresponding aryl halides. Example 5. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 280) Compound 280Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting mixture was heated to 140oC for 1.5 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine -1-carboxylate (5.8 g, 84%) as a yellow solid. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl )-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), TEA (1.2 mL, 8.3 mmol), X-Phos (0.08 g, 0.16 mmol) and Pd2(dba)3(0.15 g, 0.16 mmol). The resulting mixture was stirred at 95oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl (S)-3-methyl-4-(5- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (1.0 g, 99%) as a yellow oil. LC / MS ESI (m / z): 598 (M+H)+. Step 3. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H2O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K2CO3(1.2 g, 8.3 mmol) and Pd(dppf)Cl2(0.12 g, 0.16 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (0.69 g, 75%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 4. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d] pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (690 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.0 mL, 5.0 mmol, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (450 mg, 90%) as a white solid. LC / MS ESI (m / z): 395 (M+H)+. Step 5. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.25 mmol) in DMF (5 mL) were added 3-iodobenzonitrile (87 mg, 0.38 mmol), (1S,2S)-cyclohexane-1,2-diamine (8.6 mg, 0.076 mmol), CuI (48 mg, 0.25 mmol) and K3PO4(160 mg, 0.76 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3- cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (52 mg, 41%) as a yellow solid. LC / MS ESI (m / z): 496 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.69 (dd, J = 4.8, 0.8 Hz, 1H), 8.45 (s, 1H), 8.45 – 8.43 (m, 1H), 8.34 – 8.27 (m, 1H), 8.17 (s, 1H), 7.95 (td, J = 7.7, 1.8 Hz, 1H), 7.86 (dt, J = 7.7, 1.2 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.41 – 7.35 (m, 1H), 4.21 (d, J = 6.4 Hz, 1H), 3.77 – 3.60 (m, 2H), 3.12 – 2.55 (m, 4H), 1.36 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H). The following compounds were prepared using a procedure analogous to the synthesis of compound 280 from the corresponding aryl halides.

[0004] Example 6. Synthesis of tert-butyl (R)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 192) Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a 0oC solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (200 g, 0.71 mol) and 4-methylbenzene-1-sulfonyl chloride (180 g, 0.93 mol) in acetone (2 L) was added 2.0M NaOH (0.53 L) dropwise. After addition, the reaction was allowed to warm up to room temperature and stirred for another 3 hours. The precipitate was collected by filtration, and washed with water twice and dried under vacuum to give 4-chloro-5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidine (300 g, 95 %) as an off white solid. LC / MS ESI (m / z): 434 (M+H)+. Step 2. tert-Butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (50 g, 120 mmol) in EtOH (500 mL) was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (28 g, 140 mmol). The resulting mixture was stirred at 90oC under N2atmosphere for 16 hours. After cooling to room temperature, the solvent was removed, and the residue was quenched with H2O and EtOAc and the organic layer was separated. The aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was triturated with petroleum ether / EtOAc (10:1) and filtered to afford tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine- 1-carboxylate (48 g, 70%) as a light yellow solid. LC / MS ESI (m / z): 598 (M+H)+. Step 3. tert-Butyl (R)-4- (5- (2-fluorophenyl) -7-tosyl-7H-pyrrolo [2,3-d]pyrimidin-4- yl) -2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (300 mg, 0.50 mmol) in dioxane (10 mL) and water (1 mL) were added (2-fluorophenyl)boronic acid (77 mg, 0.55 mmol), K3PO4(210 mg, 1.0 mmol), and Pd(dppf)Cl2(37 mg, 0.050 mmol). The resulting mixture was heated to 90℃ overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (280 mg, 97%) as a white solid. LC / MS ESI (m / z): 566 (M+H)+. Step 4. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (280 mg, 0.49 mmol) in THF (6 mL) were added TBAF (3.0 mL, 1.0M in THF). The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residue was purified by flash column chromatography (silica gel, 0~64% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1- carboxylate (170 mg, 87%) as a colorless oil. LC / MS ESI (m / z): 412 (M+H)+. Step 5. tert-Butyl (R)-4-(5-(2-fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2-methylpiperazine-1-carboxylate (170 mg, 0.42 mmol) and 2-bromopyridine (79 mg, 0.50 mmol) in DMF (10 mL) were added trans-1,2-diaminocyclohexane (97 mg, 0.85 mmol), CuI (190 mg, 0.42 mmol) and K3PO4(180 mg, 0.84 mmol). The resulting mixture was stirred at 120oC for 18 hrs. After being cooled down to room temperature, the reaction partitioned between EtOAc, and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC (Gilson, C18, MeCN in water) to afford tert-butyl (R)-4-(5-(2- fluorophenyl)-7-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1- carboxylate (110 mg, 53%) as a solid. LC / MS ESI (m / z): 489 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 8.3 Hz, 1H), 8.56 (s, 1H), 8.52 – 8.48 (m, 1H), 8.25 (s, 1H), 7.90 (ddd, J = 8.4, 7.4, 1.9 Hz, 1H), 7.50 (td, J = 7.6, 1.7 Hz, 1H), 7.37 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.26 – 7.17 (m, 3H), 4.24 (s, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.67 – 3.61 (m, 1H), 3.43 (d, J = 13.2 Hz, 1H), 3.01 (dd, J = 13.0, 3.9 Hz, 1H), 2.70 (td, J = 12.3, 3.2 Hz, 1H), 2.55 (td, J = 13.0, 3.0 Hz, 1H), 1.43 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H). Example 7. Synthesis of tert-butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 226) Compound 226Step 1. tert-Butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (700 mg, 1.2 mmol, prepared following the procedure compound 259, step 1) in dioxane (10 mL) and water (1 mL) were added pyridin-3-ylboronic acid (160 mg, 1.3 mmol), Pd(dppf)Cl2(86 mg, 0.12 mmol), and K2CO3(320 mg, 2.3 mmol). The resulting mixture was heated to 90℃ overnight. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford tert-butyl (S)-3- methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 34%) as a light a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 2. tert-Butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (220 mg, 0.40 mmol) in THF (3 mL) was added TBAF (3.0 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~70% EtOAc in petroleum ether) to afford tert-butyl (S)-3- methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 78%) as a light yellow solid. LC / MS ESI (m / z): 395 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.10 mmol) and 1-fluoro-3-iodobenzene (27 mg mL, 0.12 mmol) in DMF (6 mL) were added CuI (19 mg, 0.10 mmol), K3PO4(43 mg, 0.20 mmol) and trans-1,2-diaminocyclohexane (23 mg, 0.20 mmol). The resulting mixture was stirred at 120℃ for 18 hrs. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-fluorophenyl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (20 mg, 41%) as a light yellow solid. LC / MS ESI (m / z): 489 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.72 (dt, J = 10.2, 2.2 Hz, 1H), 7.66 – 7.63 (m, 1H), 7.61 – 7.55 (m, 2H), 7.18 (tdd, J = 8.4, 2.4, 0.8 Hz, 1H), 4.07 (dt, J = 9.8, 3.1 Hz, 1H), 3.80 (d, J = 12.4 Hz, 1H), 3.50 (t, J = 12.2 Hz, 2H), 3.20 – 3.13 (m, 1H), 2.95 – 2.78 (m, 2H), 1.42 (s, 9H), 0.98 (d, J = 6.5 Hz, 3H). The following compound was prepared by the procedure analogous to the synthesis of compound 226 from the corresponding aryl halide. Example 8. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 259) Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting reaction mixture was stirred at 140℃ under N2for 2 h. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (5.8 g, 54%) as a white solid. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (1.0 g, 1.7 mmol) in toluene (20 mL) were added Pd- (dtbp)Cl2(220 mg, 0.34 mmol), K2CO3(3.0 g, 22 mmol) and cyclopropylboronic acid (220 mg, 2.5 mmol) respectively. The resulting reaction mixture was stirred at 80℃ for 4 h. After being cooled down to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (430 mg, 50%) as a white solid. LC / MS ESI (m / z): 512 (M+H)+. Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (430 mg, 0.84 mmol) in THF (10 mL) was added TBAF (4.0mL, 1.0M in THF). The resulting reaction mixture was stirred at r.t under N2overnight. The reaction mixture was quenched with ice water, then it was extracted with EtOAc twice, the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~80%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (250 mg, 83%) as a white solid. LC / MS ESI (m / z): 358 (M+H)+. Step 4. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (70 mg, 0.20 mmol) in DMF (2 mL) were added CuI (37 mg, 0.20 mmol), K3PO4(83 mg, 0.39 mmol), trans-cyclohexane-1,2-diamine (45 mL, 0.39 mmol) and 5-bromopyridine-3-carbonitrile (43 mg, 0.24 mmol) respectively. The resulting reaction mixture was stirred at 120℃ under N2overnight. After being cooled down to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) and prep-HPLC (C-18, MeCN in H2O) to afford tert-butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (28 mg, 31%) as white solid. LC / MS ESI (m / z): 460 (M+H)+.1H NMR (400 MHz, CD3OD) δ 9.33 (d, J = 2.5 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.75 – 8.72 (m, 1H), 8.36 (s, 1H), 7.42 (d, J = 0.8 Hz, 1H), 4.81 – 4.76 (m, 1H), 4.08 (d, J = 14.4 Hz, 1H), 3.97 – 3.86 (m, 2H), 3.59 – 3.52 (m, 1H), 3.49 – 3.34 (m, 1H), 3.22 – 3.10 (m, 1H), 2.11 – 2.06 (m, 1H), 1.50 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H), 1.09 – 1.04 (m, 2H), 0.93 – 0.88 (m, 1H), 0.82 – 0.76 (m, 1H). The following compounds were prepared by the procedures analogous to the synthesis of compound 259 from the corresponding aryl halides.

[0005] Example 9. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 266) Step 1. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-isocyanopyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (110 mg, 0.31 mmol) in DMF (3 mL) were added CuI (29 mg, 0.15 mmol), K3PO4(200 mg, 0.92 mmol), trans-cyclohexane-1,2-diamine (22 mg, 0.18 mmol) and 2-bromopyridine-4-carbonitrile (140 mg, 0.62 mmol) respectively. The resulting reaction mixture was stirred at 120℃ under N2 overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 98%) as white solid. LC / MS ESI (m / z): 459 (M+H)+. Step 2. (S)-3-(5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)benzonitrile To the solution of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (140 mg, 0.30 mmol) in DCM (1 mL) was added TFA (0.50 mL, 6.7 mmol). The resulting reaction mixture was stirred at room temp under N2overnight. Solvent was removed and the residue was diluted with DCM, washed with sat. NaHCO3, organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product which was used in the next step without further purification. LC / MS ESI (m / z): 359 (M+H)+. Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of (S)-3-(5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)benzonitrile (75 mg, 0.21 mmol) in DMF (3 mL) were added DIPEA (0.20 mL, 1.0 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl-1H-imidazole-1-carboxylate (120 mg, 0.52 mmol, prepared from 1,1,1-trifluoro-2-methylpropan-2-ol and CDI) respectively. The resulting reaction mixture was stirred at 80℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water. the organic layer was separated, and the aqueous layer was extracted EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to afford 1,1,1-trifluoro-2- methylpropan-2-yl (S)-4-(7-(3-cyanophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (37 mg, 34%) as a white solid. LC / MS ESI (m / z): 513 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 8.22 – 8.20 (m, 1H), 8.07 – 8.04 (m, 1H), 7.72 – 7.68 (m, 2H), 7.32 (d, J = 0.6 Hz, 1H), 4.80 (s, 1H), 4.14 – 3.92 (m, 2H), 3.89 – 3.82 (m, 1H), 3.61 – 3.54 (m, 1H), 3.50 – 3.36 (m, 1H), 2.12 – 2.06 (m, 1H), 2.03 (s, 1H), 1.72 (d, J = 6.3 Hz, 6H), 1.22 (d, J = 6.5 Hz, 3H), 1.07 – 1.03 (m, 2H), 0.91 – 0.75 (m, 2H). The following compounds were prepared by the procedures analogous to the synthesis of compound 266 from the corresponding aryl halides.

[0006] Example 10. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-cyanopyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 274) Compound 274Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (400 mL) were added (3-chlorophenyl)boronic acid (8.7 g, 72 mmol), 4Å molecular sieves (5 g), Cu(OAc)2(16 g, 89 mmol) and pyridine (17 mL, 210 mmol). The resulting mixture was stirred at room temperature under O2atmosphere for 48 hours. The reaction was quenched with NH4OH (30 mL) and ice water and filtered. The filtrate was extracted with DCM twice, the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.5 g, 54%) as a white solid. LC / MS ESI (m / z): 390 (M+H)+. Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate To the solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 6.4 mmol) in DIEA (8 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (3.2 g, 16 mmol). The resulting reaction mixture was stirred at 140℃ under N2for 2 h. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (3.0 g, 84%) as a white solid. LC / MS ESI (m / z): 554 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (2.5 g, 4.6 mmol) in dioxane (15 mL) were added X-Phos (220 mg, 0.46 mmol), Pd(dba)3(0.40 g, 0.46 mmol) and 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.7 mL, 18 mmol) respectively. The resulting reaction mixture was stirred at 95℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was quenched with ice water, extracted with DCM twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate (3.5 g) as a yellow oil that was used directly in the next step. LC / MS ESI (m / z): 554 (M+H)+. Step 4. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (70 mg, 0.13 mmol) in dioxane (2 mL) and H2O (0.4 mL) were added K2CO3(87 mg, 0.63 mmol), Pd(dppf)Cl2(10 mg, 0.01 mmol) and 3-bromopyrazine-2-carbonitrile (47 mg, 0.25 mmol) respectively. The resulting reaction mixture was stirred at 90℃ under N2overnight. After being cooled down to room temperature the solvent was removed. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) and prep-HPLC (Gilson, C-18, MeCN in H2O) to afford tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(3-cyanopyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (32 mg, 48%) as a white solid. LC / MS ESI (m / z): 531 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 7.79 (s, 2H), 7.70 – 7.66 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.45 – 7.41 (m, 1H), 4.38 – 3.95 (m, 1H), 3.85 – 3.78 (m, 1H), 3.65 – 3.58 (m, 1H), 3.53 – 3.25 (m, 1H), 3.20 – 2.87 (m, 2H), 2.66 (s, 1H), 1.44 (s, 9H), 1.18 – 0.96 (m, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 274 from the corresponding aryl halides.

[0007] Example 11. Synthesis of tert-butyl (R)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 388) Compound 388Step 1.5-Bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 21 mmol) in acetone (70 mL) was added TsCl (4.1 g, 21 mmol). The mixture was cooled to 0°C. Then, 2M NaOH solution (13 mL) was added. After the addition, the mixture was stirred at rt for 3 h. The mixture was diluted with water and was filtered. The filter cake was washed with water and dried under vacuum to provide 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (7.4 g, 88%) as a white solid. LC / MS ESI (m / z): 386 (M+H)+. Step 2. tert-Butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate A mixture of 5-bromo-4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.8 mmol), tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.9 g, 9.3 mmol) and DIPEA (3.9 mL, 24 mmol) in EtOH (20 mL) was stirred at 100°C overnight. The mixture was cooled to rt and filtered. The filter cake was washed with EtOH and dried under vacuum to provide tert- butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1- carboxylate (3.7 g, 86%) as a white solid. LC / MS ESI (m / z): 550 (M+H)+. Step 3. tert-Butyl (R)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate tert-Butyl (R)-4-(5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (3.7 g, 6.7 mmol) was treated with TBAF (16 mL, 1.0 M in THF) at rt for 2 h. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to provide tert-butyl (R)-4-(5-bromo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (2.1 g, 77%) as a light yellow solid. LC / MS ESI (m / z): 396 (M+H)+. Step 4. tert-Butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate tert-Butyl (R)-4-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2 -methylpiperazine- 1- carboxylate (2.1 g, 5.2 mmol), K3PO4(2.2 g, 10 mmol ), CuI (0.99 g, 5.2 mmol) and 2- bromo-4-chloropyridine (1.5 g, 7.8 mmol) were mixed in dry DMF (50 mL). trans- dimethylcyclohexane-1,2-diamine (0.74 g, 5.2 mmol) was then added, and the mixture was stirred at 90°C under N2for 2.5 h. Then it was diluted with EtOAc, washed with LiCl (5% aq. solution) and brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0~15% EtOAc in petroleum ether) to provide tert-butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (2.1 g, 79%). LC / MS ESI (m / z): 507 (M+H)+. Step 5. tert-Butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To tert-butyl (R)-4-(5-bromo-7-(4-chloropyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin-4- yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.59 mmol) and azetidin-2-one (130 mg, 1.8 mmol) were added K3PO4(250 mg, 1.2 mmol), CuI (110 mg, 0.59 mmol), dry DMF (5 mL) and trans-dimethylcyclohexane-1,2-diamine (170 mg, 1.2 mmol). The mixture was stirred at 90°C under N2overnight. It was then diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (0~60% EtOAc in petroleum ether, then 0~7% MeOH in DCM) to provide tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (170 mg, 58%) as a pale yellow solid. LC / MS ESI (m / z): 498 (M+H)+. Step 6. tert-Butyl (R)-4-(5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To tert-butyl (R)-4-(7-(4-chloropyridin-2-yl)-5-(2-oxoazetidin-1-yl)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (65 mg, 0.13 mmol) in dry THF (4 mL) was added RhH(CO)(PPh3)3(32 mg, 0.035 mmol). The mixture was purged with N2. Then PhSiH3(70 mg, 0.65 mmol) was added. The mixture was stirred at 60°C under N2for 2 h and was then concentrated and purified by prep-TLC (petroleum ether / EtOAc = 5:1, v / v) to provide tert-butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methylpiperazine-1-carboxylate (50 mg, 79%) as a light yellow oil. LC / MS ESI (m / z): 484 (M+H)+. Step 7. tert-Butyl (R)-4-(5-(azetidin-1-yl)-7-(4-cyanopyridin-2-yl)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To Zn(CN)2(75 mg, 0.64 mmol) and Pd(PPh3)4(75 mg, 0.065 mmol) was added tert- butyl (2R)-4-[5-(azetidin-1-yl)-7-(4-chloropyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]-2- methylpiperazine-1-carboxylate (62 mg, 0.13 mmol) in dry DMF (3 mL). The mixture was stirred at 120°C under N2overnight. Then it was diluted with EtOAc, washed with 5% LiCl (aq) and brine, dried over Na2SO4and concentrated. The residue was purified by prep-TLC (petroleum ether / EtOAc = 3:1, v / v) to provide tert-butyl (R)-4-(5-(azetidin-1-yl)-7-(4- cyanopyridin-2-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (16 mg, 26%) as a yellow solid. LC / MS ESI (m / z): 475 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 7.46 (s, 1H), 7.29 (dd, J = 5.0, 1.1 Hz, 1H), 4.76 (d, J = 12.6 Hz, 1H), 4.46 (d, J = 13.4 Hz, 1H), 4.40 – 4.29 (m, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.83 (q, J = 6.9 Hz, 2H), 3.64 (q, J = 6.9 Hz, 2H), 3.46 – 3.33 (m, 2H), 3.02 (td, J = 12.4, 3.4 Hz, 1H), 2.29 (p, J = 7.1 Hz, 2H), 1.49 (s, 9H), 1.02 (d, J = 6.8 Hz, 3H).

[0008] Example 12. Synthesis of tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Compound 392) Compound 392Step1.4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1.1 g, 2.5 mmol) in DMF (15 mL) and water (0.5 mL) were added (2-fluorophenyl)boronic acid (420 mg, 0.60 mmol), X-Phos (180 mg, 0.37 mmol), K3PO4(1.6 g, 7.5 mmol) and Pd2(dba)3(230 mg, 0.25 mmol), and the resulting mixture was heated to 60oC overnight. After being cooled down to room temperature, the reaction mixture was filtered. The filtrate was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to afford 4-chloro-5-(2-fluorophenyl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidine (600 mg, 60%). LC / MS ESI (m / z): 402 (M+H)+. Step 2. tert-Butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 2.2 mmol) in EtOH (6 mL) were added DIEA (0.66 mL, 4.0 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (440 mg, 2.1 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate (660 mg, 70%) as a white solid. LC / MS ESI (m / z): 578 (M+H)+. Step 3. tert-Butyl 7-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (660 mg, 1.6 mmol) in THF (10 mL) was added TBAF (6.5 mL, 1.0 M in THF). The resulting reaction mixture was stirred at room temp under N2overnight. The reaction mixture was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(5- (2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -4,7-diazaspiro[2.5]octane-4-carboxylate (410 mg, 62%) as a white solid. LC / MS ESI (m / z): 424 (M+H)+. Step 4. tert-Butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To the solution of tert-butyl 7-(5-(2-fluorophenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)- 4,7-diazaspiro[2.5]octane-4-carboxylate (400 mg, 0.95 mmol) in DMF (10 mL) were added CuI (90 mg, 0.47 mmol), K3PO4(600 mg, 2.9 mmol), trans-cyclohexane-1,2-diamine (0.030 mL, 0.28 mmol) and 2-bromoisonicotinonitrile (350 mg, 1.9 mmol), respectively. The resulting reaction mixture was stirred at 80℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (450 mg, 91%) as white solid. LC / MS ESI (m / z): 526 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.63 – 8.60 (m, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.50 – 7.46 (m, 1H), 7.41 – 7.35 (m, 2H), 7.28 –7.18 (m, 2H), 3.28 (s, 2H), 3.21 (s, 2H), 3.12 (s, 2H), 1.42 (s, 9H), 0.93 – 0.88 (m, 2H), 0.74 (s, 2H). Example 13. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((R)-2- (hydroxymethyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate (Compound 312) Compound 312To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (460 mg, 0.83 mmol) in DMSO (5 mL) were added CuI (32 mg, 0.17 mmol), L-Proline (38 mg, 0.30 mmol), K2CO3(340 mg, 2.5 mmol) and (R)-pyrrolidin-2-ylmethanol (0.33 mL, 3.3 mmol) respectively. The resulting reaction mixture was stirred at 70℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated and the aqueous was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) followed by prep-HPLC (Gilson, C-18, MeCN in water) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (100 mg, 23%) as a solid. LC / MS ESI (m / z): 527 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.74 – 7.68 (m, 1H), 7.67 – 7.62 (m, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.33 – 7.28 (m, 1H), 6.90 (s, 1H), 5.19 – 5.01 (m, 1H), 4.23 – 3.92 (m, 3H), 3.91 – 3.82 (m, 1H), 3.79 – 3.69 (m, 2H), 3.65 – 3.61 (m, 1H), 3.55 – 3.43 (m, 2H), 3.41 – 3.29 (m, 1H), 3.04 – 2.89 (m, 1H), 2.82 – 2.74 (m, 1H), 2.19 – 2.12 (m, 1H), 2.00 – 1.88 (m, 3H), 1.49 (s, 9H), 1.18 – 1.04 (m, 3H). Example 14. Synthesis of tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (Compound 396) Compound 396Step 1. tert-Butyl 7-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5] octane-4-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (750 mg, 2.7 mmol, prepared following the procedure of compound 192, step 1) in EtOH (5 mL) were added DIEA (0.90 mL, 5.5 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (550 mg, 2.6 mmol), respectively. The resulting reaction mixture was stirred at 100℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(5- iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (920 mg, 75%) as white solid. LC / MS ESI (m / z): 610 (M+H)+. Step 2. tert-Butyl 7-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate To the solution of tert-butyl 7-(5-iodo-7-tosyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (900 mg, 2.0 mmol) in toluene (12 mL) were added Pd- 118 (97 mg, 0.15 mmol), K2CO3(2.6 g, 19 mmol) and cyclopropylboronic acid (190 mg, 2.2 mmol) respectively. The resulting reaction mixture was stirred at 80℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford tert-butyl 7-(5-cyclopropyl-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (240 mg, 33%) as white solid. LC / MS ESI (m / z): 524 (M+H)+. Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the solution of tert-butyl 7-(5-cyclopropyl-7-tosyl-7H-pyrrolo [2,3-d]pyrimidin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (240 mg, 0.65 mmol) in THF (4 mL) was added TBAF (2.4 mL, 1.0 M in THF). The resulting reaction mixture was stirred at rt under N2overnight. The reaction mixture was quenched with ice water, and extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to obtain tert-butyl 7-(5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 62%) as a white solid. LC / MS ESI (m / z): 370 (M+H)+. Step 4. tert-Butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate To a solution of tert-butyl 7-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (150 mg, 0.41 mmol) in DMF (5 mL) were added CuI (39 mg, 0.21 mmol), K3PO4(260 mg, 1.2 mmol), trans-cyclohexane-1,2-diamine (0.020 mL, 0.12 mmol) and 2-bromoisonicotinonitrile (150 mg, 0.81 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) and prep-HPLC to afford tert-butyl 7-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (100 mg, 54%) as white solid. LC / MS ESI (m / z): 472 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.59 – 8.56 (m, 1H), 8.47 (s, 1H), 7.77 (d, J = 0.7 Hz, 1H), 7.35 – 7.32 (m, 1H), 3.87 – 3.81 (m, 2H), 3.77 – 3.73 (m, 2H), 3.61 (s, 2H), 2.02 – 1.95 (m, 1H), 1.50 (s, 9H), 1.06 – 0.98 (m, 4H), 0.83 – 0.78 (m, 4H). Example 15. Synthesis of tert-butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 404) Step 1. tert-Butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (1.0 g, 1.7 mmol) in dioxane (20 mL) and water (0.5 mL) were added Pd(dppf)Cl2(140 mg, 0.17 mmol), K2CO3(930 mg, 6.7 mmol) and (2- fluorophenyl)boronic acid (280 mg, 2.0 mmol). The resulting reaction mixture was stirred at 90℃ overnight. After being cooled down to room temperature, solvent was removed, the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to obtain tert-butyl (S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (810 mg, 85%) as a white solid. LC / MS ESI (m / z): 566 (M+H)+. Step 2. tert-Butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To the solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (570 mg, 1.0 mmol) in THF (4 mL) was added TBAF (4.0 mL, 1.0M in THF). The resulting reaction mixture was stirred at room temperature under N2overnight. The reaction mixture was quenched with ice water, then it was extracted with EtOAc twice, the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to obtain tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-3- methylpiperazine -1-carboxylate (330 mg, 80%) as a white solid. LC / MS ESI (m / z): 412 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl) -7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate In a sealed tube, tert-butyl (S)-4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (150 mg, 0.37 mmol), 2,6-dibromoisonicotinonitrile (190 mg, 0.73 mmol), K3PO4(160 mg, 0.73 mmol) and CuI (69 mg, 0.36 mmol) were mixed in dry DMF. Then (±)-trans-1,2-cyclohexanediamine (100 mg, 0.73 mmol) was added. The mixture was stirred at 90°C under N2for 3.5 h and was cooled to rt. Then it was diluted with EtOAc, washed with 5% LiCl (aq.) and brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0~11% EtOAc in petroleum ether) to provide tert-butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 55%) as a yellow foam. LC / MS ESI (m / z): 592 (M+H)+. Step 4. tert-Butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2-fluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(6-bromo-4-cyanopyridin-2-yl)-5-(2-fluorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.20 mmol), methylboronic acid (98 mg, 1.6 mmol), Cs2CO3(200 mg, 0.61 mmol) and Pd(dppf)Cl2(20 mg, 0.027 mmol) in dioxane (3 mL) and H2O (0.6 mL) was stirred at 100°C under N2overnight. Then it was diluted with EtOAc and DCM and was filtered. The filtrate was purified by flash column chromatography (silica gel, 0~20% EtOAc in petroleum ether followed by prep-HPLC to provide tert-butyl (S)-4-(7-(4-cyano-6-methylpyridin-2-yl)-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (23 mg, 21%) as a light yellow oil. LC / MS ESI (m / z): 528 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.46 (td, J = 7.6, 1.5 Hz, 1H), 7.37 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.26 – 7.17 (m, 3H), 4.32 – 4.06 (m, 1H), 3.86 – 3.61 (m, 1H), 3.56 – 3.42 (m, 2H), 3.08 (td, J = 12.3, 2.5 Hz, 1H), 2.87 – 2.59 (m, 5H), 1.43 (s, 9H), 1.01 (d, J = 5.7 Hz, 3H). The following compound was prepared by a synthetic procedure similar to that described for compound 404, except using tert-butyl (S)-4-(5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. Example 16. Synthesis of tert-butyl (1S,6R)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (Compound 408) and tert-butyl (1R,6S)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (Compound 409) Step 1. tert-Butyl 5-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate To the solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.87 mmol, prepared following the procedure of compound 192, step 1) in EtOH (5 mL) were added DIEA (0.14 mL, 0.87 mmol) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2- carboxylate (140 mg, 0.72 mmol) respectively. The resulting reaction mixture was stirred at 100℃ under N2overnight. After removal of solvent, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5-(5- cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2- carboxylate (140 mg, 45%) as white solid. LC / MS ESI (m / z): 510 (M+H)+. Step 2. tert-Butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate To the solution of tert-butyl 5-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (140 mg, 0.40 mmol) in THF (2 mL) were added TBAF (1.5 mL, 1.0M in THF). The resulting reaction mixture was stirred at room temperature under N2overnight. The reaction mixture was quenched with ice water and extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert- butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2- carboxylate (90 mg, 64%) as a white solid. LC / MS ESI (m / z): 356 (M+H)+. Step 3. tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate To the solution of tert-butyl 5-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (90 mg, 0.25 mmol) in DMF (6 mL) were added CuI (24 mg, 0.13 mmol), K3PO4(160 mg, 0.75 mmol), trans-cyclohexane-1,2-diamine (9.0 mg, 0.080 mmol) and 2-bromoisonicotinonitrile (93 mg, 0.51 mmol) respectively. The resulting reaction mixture was stirred at 80℃ under N2overnight. After being cooled down to room temperature, the reaction mixture was partitioned between EtOAc and water, organic layer was separated, the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether), prep-HPLC (Gilson, C18, MeCN in water) to afford tert-butyl 5-(7-(4- cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (60 mg, 53%) as white solid. LC / MS ESI (m / z):458 (M+H)+. Step 4. tert-Butyl (1S,6R)-5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate and tert-butyl (1R,6S)-5-(7- (4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylatePreparative separation method: Instrument: Waters Thar 80 preparative SFC; Column: ChiralCel OJ, 250×21.2mm I.D., 5µm; Mobile phase: A for CO2 and B for MEOH+0.1%NH3H2O; Gradient: B 40%; Flow rate: 50mL / min; Back pressure: 100 bar; Column temperature: 35℃; Wavelength: 254nm; Cycle-time: 7min; Eluting time: 1.5H tert-Butyl 5-(7-(4-cyanopyridin-2-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- diazabicyclo[4.1.0]heptane-2-carboxylate (60 mg) was separated by SFC to give two isomers: Peak 1: shorter retention time, 22 mg as white solid. LC / MS ESI (m / z): 458 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.33 (d, J = 3.2 Hz, 1H), 8.60 – 8.57 (m, 1H), 8.46 – 8.39 (m, 1H), 7.85 – 7.81 (m, 1H), 7.36 – 7.32 (m, 1H), 4.55 – 4.46 (m, 1H), 3.84 – 3.74 (m, 1H), 3.67 – 3.39 (m, 3H), 3.10 – 2.98 (m, 1H), 2.07 – 1.99 (m, 1H), 1.48 (s, 9H), 1.22 – 1.12 (m, 1H), 1.00 – 0.74 (m, 4H), 0.50 – 0.44 (m, 1H). Peak 2: longer retention time, 24 mg as white solid. LC / MS ESI (m / z): 458 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.37 – 9.29 (m, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.45 – 8.40 (m, 1H), 7.85 – 7.81 (m, 1H), 7.34 (dd, J = 5.0, 1.3 Hz, 1H), 4.55 – 4.46 (m, 1H), 3.84 – 3.75 (m, 1H), 3.67 – 3.60 (m, 0.5H), 3.56 – 3.46 (m, 1H), 3.45 – 3.36 (m, 1.5H), 3.10 – 2.98 (m, 1H), 2.07 – 2.00 (m, 1H), 1.48 (s, 9H), 1.21 – 1.13 (m, 1H), 0.99 – 0.90 (m, 2H), 0.82 – 0.68 (m, 2H), 0.50 – 0.44 (m, 1H).

[0009] Example 17. Synthesis of ethyl 4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 1003) Compound 1003Step 1.4-Chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 23 mmol, prepared following the procedure of compound 192, step 1) in dioxane-H2O (100 mL, v / v=5 / 1) were added (2-fluorophenyl)boronic acid (3.3 g, 23 mmol), K3PO4(9.8 g, 46 mmol) and Pd(dppf)Cl2(1.7 g, 2.3 mmol). The resulting mixture was heated to 60oC overnight. After being cooled down to room temperature, the reaction was filtered, filtrate was partitioned between EtOAc and water, organic layer was separated, the aqueous phase was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidine (7.0 g, 75% yield) as a solid. LC / MS ESI (m / z): 402 (M+H)+. Step 2.4-Chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine To a 0oC solution of 4-chloro-5-(2-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidine (1.0 g, 2.50 mmol) in THF (5 mL) was added TBAF (7.5 mL, 1.0M in THF). The resulting mixture was stirred at the same temperature for 5 h. The reaction was quenched with ice water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60% ethyl acetate in petroleum ether) to afford 4-chloro-5-(2- fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (530 mg, 85%) LC / MS ESI (m / z): 248 (M+H)+. Step 3.4-Chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidine To a solution of 4-chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (530 mg, 2.1 mmol) in toluene (20 mL) were added 3-iodo-5-methoxypyridine (600 mg, 2.6 mmol), CuI (81 mg, 0.40 mmol), 1,10-phenanthroline (77 mg, 0.40 mmol) and Cs2CO3(2.1 g, 6.4 mmol). The resulting mixture was heated to 110oC under N2overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidine (400 mg, 53%) as a yellow solid. LC / MS ESI (m / z): 355 (M+H)+. Step 4. Ethyl 4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of 4-chloro-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidine (100 mg, 0.30 mmol) in EtOH (10 mL) were added ethyl piperazine-1-carboxylate (63 mg, 0.30 mmol) and DIPEA (110 mg, 0.90 mmol). The resulting mixture was heated to 100oC under N2overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford ethyl 4-(5-(2- fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (50 mg, 37%) as a white solid, which was further purified by prep-HPLC to afford 22.8 mg of white solid. LC / MS ESI (m / z): 477 (M+H)+.1H NMR (400 MHz, DMSO- d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 7.94 (t, J = 2.3 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.52 – 7.46 (m, 1H), 7.41 – 7.36 (m, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.24 – 3.20 (m, 4H), 3.16 – 3.09 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H). The following compound was prepared by the procedure analogous to the synthesis of compound 1003 from the corresponding amine. Example 18. Synthesis of tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 151) Compound 151Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a 0°C solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (200 g, 0.71 mol) and 4-methylbenzene-1-sulfonyl chloride (180 g, 0.93 mol) in acetone (2 L) was added dropwise 2.0M NaOH (0.53 L). After addition, the reaction was allowed to warm up to room temperature and stirred for another 3 hours. The precipitate was collected by filtration and washed with water twice and dried in vacuo to afford 4-chloro-5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidine (300 g, 95 %) as an off white solid. LC / MS ESI (m / z): 434 (M+H)+. Step 2. tert-Butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate A mixture of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.6 g, 11 mmol), tert-butyl piperazine-1-carboxylate (2.2 g, 12 mmol) and DIPEA (2.8 mL, 16 mmol) in EtOH (20 mL) was stirred at 100°C overnight. After being cooled down to r.t, solvent was removed and the residue was purified by flash column chromatography to provide tert-butyl 4-(5-iodo- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (5.5 g, 89%) as a white solid. LC / MS ESI (m / z): 584 (M+H)+. Step 3. tert-Butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (300 mg, 0.51 mmol) in dioxane (5 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.30 mL, 2.0 mmol), TEA (0.35 mL, 2.5 mmol), X-Phos (25 mg, 0.052 mmol) and Pd2(dba)3(47 mg, 0.052 mmol). The resulting mixture was stirred at 95oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl 4-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (300 mg, 99%) as a yellow oil. LC / MS ESI (m / z): 584 (M+H)+. Step 4. tert-Butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.51 mmol) in dioxane (5 mL) and H2O (1 mL) were added 2-bromopyridine (0.96 mL, 1.0 mmol), K2CO3(360 mg, 2.5 mmol) and Pd(dppf)Cl2(38 mg, 0.052 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate (180 mg, 65%) as a white solid. LC / MS ESI (m / z): 535 (M+H)+. Step 5. tert-Butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate To a solution of tert-butyl 4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (180 mg, 0.33 mmol) in THF (2 mL) was added TBAF (2.0 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 93%) as a white solid. LC / MS ESI (m / z): 381 (M+H)+. Step 6. tert-Butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (120 mg, 0.31 mmol) in DMF (10 mL) was added 2-chloro-1- fluoro-4-iodobenzene (0.048 mL, 0.37 mmol), trans-cyclohexane-1,2-diamine (11 mg, 0.095 mmol), CuI (18 mg, 0.095 mmol) and K3PO4(200 mg, 0.94 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (130 mg, 80%) as a white solid. LC / MS ESI (m / z): 509 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.3 Hz, 1H), 8.52 (s, 1H), 7.85 (dd, J = 6.4, 2.6 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (s, 1H), 7.67 – 7.60 (m, 2H), 7.34 – 7.23 (m, 2H), 3.35 (d, J = 17.5 Hz, 8H), 1.44 (s, 9H). The following compound was prepared by analogous procedures to the synthesis of compound 151 from the corresponding amines and aryl halides.

[0010] Example 19. Synthesis of ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 152) Compound 152Step 1.7-(3-Chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.19 mmol, prepared following the procedure of compound 151 in DCM (3 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 3h. After removal of solvent, the residue was diluted with DCM, washed with NaHCO3(aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly, 7-(3- chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine. LC / MS ESI (m / z): 409 (M+H)+. Step 2. Ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a 0oC solution of 7-(3-chloro-4-fluorophenyl)-4-(piperazin-1-yl)-5-(pyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.19 mmol) in DCM (3 mL) were added dropwise ethyl carbonochloridate (0.040 mL, 0.39 mmol) and TEA (0.080 mL, 0.58 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl 4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 30%) as a white solid. LC / MS ESI (m / z): 481 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.72 – 8.66 (m, 1H), 8.53 (s, 1H), 7.85 (dd, J = 6.4, 2.6 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 – 7.59 (m, 3H), 7.34 – 7.24 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.38 (s, 8H), 1.24 (t, J = 7.1 Hz, 3H). Example 20. Synthesis of tert-butyl 4-(7-(5-chloropyridin-3-yl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 164) Compound 164Step 1.4-Chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.8 g, 13 mmol, prepared following the procedure of compound 151, step 1) toluene (50 mL) were added cyclopropylboronic acid (1.1 g, 13 mmol), K2CO3(24 g, 170 mmol) and Pd-118 (880 mg, 1.3 mmol). The resulting mixture was heated to 80oC overnight. After being cooled down to room temperature, solvent was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give 4- chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3.6 g, 77% yield) as a solid. LC / MS ESI (m / z): 348 (M+H)+. Step 2. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate The mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.4 mmol) and tert-butyl 3-methylpiperazine-1-carboxylate (1200 mg, 5.7 mmol) was heated to 150oC for 3 h. After being cooled down to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (450 mg, 61%) as a white solid. LC / MS ESI (m / z): 512 (M+H)+. Step 3. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (450 mg, 0.88 mmol) in THF (5 mL) was added TBAF (5.3 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (240 mg, 76%) as a yellow solid. LC / MS ESI (m / z): 358 (M+H)+. Step 4. tert-Butyl 4-(7-(5-chloropyridin-3-yl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (120 mg, 0.33 mmol) in DMF (5 mL) were added 3-bromo- 5-chloropyridine (78 mg, 0.40 mmol), trans-cyclohexane-1,2-diamine (12 mg, 0.10 mmol), CuI (19 mg, 0.10 mmol) and K3PO4(210 mg, 1.0 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature, the reaction was diluted with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4-(7-(5-chloropyridin-3-yl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (53 mg, 33%) as a white solid. LC / MS ESI (m / z): 469 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.26 (t, J = 2.1 Hz, 1H), 6.94 (s, 1H), 4.76 (s, 1H), 4.19 – 3.79 (m, 3H), 3.56 (t, J = 12.0 Hz, 1H), 3.37 – 3.03 (m, 2H), 2.06 – 1.99 (m, 1H), 1.50 (s, 9H), 1.25 (d, J = 6.5 Hz, 3H), 1.04 (dd, J = 8.1, 1.7 Hz, 2H), 0.85 – 0.77 (m, 1H), 0.76 – 0.67 (m, 1H). The following compounds were prepared by analogous procedures to the synthesis of compound 164 from the corresponding amines and aryl halides. Example 21. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 267) Step 1. tert-Butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine- 1-carboxylate A solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol, prepared following the procedures of step 1 of compound 259 synthesis) in THF (5 mL) at 0oC was treated with TBAF (6.7 mL, 1.0M in THF). The resulting mixture was stirred at 0oC for 3h. The reaction was quenched with water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~70%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.55 g, 74%) as a yellow solid. LC / MS ESI (m / z): 444 (M+H)+. Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (550 mg, 1.2 mmol) in DCM (15 mL) were added (3- chlorophenyl)boronic acid (390 mg, 2.4 mmol), Cu(OAc)2(670 mg, 3.7 mmol), pyridine (0.60 mL, 7.4 mmol) and 4A molecular sieves (400 mg). The resulting mixture was stirred at 40℃ under an O2atmosphere overnight. After cooling in an ice-water bath, the reaction was quenched with aq. NH4OH (2 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (240 mg, 35%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (240 mg, 0.43 mmol) in dioxane (10 mL) were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 mL, 1.7 mmol), TEA (0.30 mL, 2.1 mmol), X-Phos (21 mg, 0.043 mmol) and Pd2(dba)3(40 mg, 0.043 mmol). The resulting mixture was stirred at 95oC overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl (S)-4-(7-(3-chlorophenyl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate as a yellow oil, which was used in the next step directly. LC / MS ESI (m / z): 554 (M+H)+. Step 4. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.21 mmol) in dioxane (5 mL) and H2O (1 mL) were added 2-bromo-3-fluoropyrazine (77 mg, 0.43 mmol), K2CO3(150 mg, 1.0 mmol) and Pd(dppf)Cl2(16 mg, 0.022 mmol). The resulting mixture was heated at 90oC overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(3-fluoropyrazin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (59 mg, 51%) as a white solid. LC / MS ESI (m / z): 524 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 3.9, 2.6 Hz, 1H), 8.52 (s, 1H), 8.21 – 8.14 (m, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.43 – 7.38 (m, 1H), 4.62 – 4.24 (m, 1H), 3.88 – 3.72 (m, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.60 – 3.39 (m, 1H), 3.18 – 2.64 (m, 3H), 1.44 (s, 9H), 1.13 (d, J = 13.8 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 267 using the corresponding aryl halide. Example 22. Synthesis of tert-butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H- pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (Compound 171) Compound 171Step 1.4-Chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a 0oC suspension of NaH (400 mg, 10 mmol, 60 wt % in mineral oil) in anhydrous DMF (30 mL) was added 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (1.4 g, 5.0 mmol, prepared following the procedure for compound 418, step 1) in portions, followed by 4- methylbenzenesulfonyl chloride (1.1 g, 6.0 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The reaction was poured into ice water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (1.7 g, 80%) as a light yellow solid. LC / MS ESI (m / z): 433 (M+H)+. Step 2.4-Chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (920 mg, 2.1 mmol) in dioxane (10 mL) and H2O (2 mL) was added (2-fluorophenyl)boronic acid (300 mg, 2.1 mmol), K2CO3(880 mg, 6.3 mmol) and Pd(dppf)Cl2(160 mg, 0.21 mmol). The resulting mixture was heated at 90oC overnight. After being cooled to room temperature, the solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-3-(2-fluorophenyl)-1- tosyl-1H-pyrrolo[3,2-c]pyridine (680 mg, 79%) as a white solid. LC / MS ESI (m / z): 401 (M+H)+. Step 3.4-Chloro-3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (680 mg, 1.7 mmol) in THF (5 mL) was added TBAF (10 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 4-chloro-3-(2-fluorophenyl)- 1H-pyrrolo[3,2-c]pyridine (410 mg, 97%) as a white solid. LC / MS ESI (m / z): 247 (M+H)+. Step 4.4-Chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine To a solution of 4-chloro-3-(2-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (410 mg, 1.6 mmol) in DMF (15 mL) were added 5-iodopyrimidine (690 mg, 3.3 mmol), trans- cyclohexane-1,2-diamine (57 mg, 0.49 mmol), CuI (320 mg, 1.6 mmol) and K3PO4(1.1 mg, 4.9 mmol). The resulting mixture was heated at 120oC overnight. After cooling to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 4-chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2- c]pyridine (70 mg, 13%) as a yellow oil. LC / MS ESI (m / z): 325 (M+H)+. Step 5. tert-Butyl 4-(3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin- 4-yl)piperazine-1-carboxylate 4-chloro-3-(2-fluorophenyl)-1-(pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine (70 mg, 0.21 mmol) and tert-butyl piperazine-1-carboxylate (200 mg, 1.0 mmol).was heated at 150oC for 3 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4-(3-(2-fluorophenyl)-1- (pyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate (2.5 mg, 2.0%) as a white solid. LC / MS ESI (m / z): 475 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 9.00 (s, 2H), 8.12 (d, J = 5.9 Hz, 1H), 7.54 (td, J = 7.7, 1.8 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.35 (d, J = 0.7 Hz, 1H), 7.25 – 7.17 (m, 2H), 7.08 (d, J = 5.9 Hz, 1H), 3.05 (s, 8H), 1.43 (s, 9H). Example 23. Synthesis of 1-fluoro-2-methylpropan-2-yl 4-(5-(2-fluorophenyl)-7- (pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 172) Compound 172Step 1.1-Fluoro-2-methylpropan-2-ol To a -60°C solution of ethyl 2-fluoroacetate (10 g, 94 mmol) in dry THF (30 mL) under N2was added CH3MgBr (210 mL, 1.0 M in THF, 210 mmol) dropwise. The mixture was kept at the same temperature for 1 h and then at 0°C for 4 h. It was quenched by addition of 50 mL of ice water, and conc. HCl (18 mL) and solid NaCl (10 g) in sequence. The mixture was extracted with DCM. The organic layer was dried over Na2SO4overnight, and concentrated by rotary evaporation, keeping the bath temperature below 25°C. The residue was purified by distillation under normal pressure to afford 1-fluoro-2-methylpropan-2-ol (3.5 g, 40%) as a colorless liquid (bp ~ 92°C).1H NMR (400 MHz, CDCl3) δ 4.20 (d, J = 47.7 Hz, 2H), 1.25 (t, J = 2.6 Hz, 6H), hydroxyl group proton exchanged. Step 2.1-Fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To CDI (530 mg, 3.3 mmol) in dry DCM (8 mL) under N2was added 1-fluoro-2- methylpropan-2-ol (300 mg, 3.3 mmol) dropwise. The mixture was stirred at rt overnight. It was then diluted with DCM, washed with water and brine, dried over Na2SO4and concentrated to provide 1-fluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (290 mg, 47%) as a colorless oil. LC / MS ESI (m / z): 187 (M+H)+. Step 3. tert-Butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate A mixture of 4-chloro-5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (580 mg, 2.3 mmol), tert-butyl piperazine-1-carboxylate (520 mg, 2.8 mmol, prepared following the procedure of compound 1003, first two steps) and DIPEA (1.6 mL, 9.7 mmol) in EtOH (10 mL) was stirred at 100 °C overnight. The solvents were removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether, then 100% DCM) to provide tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (560 mg, 60%) as a light yellow solid. LC / MS ESI (m / z): 398 (M+H)+. Step 4. tert-Butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)piperazine-1-carboxylate To tert-butyl 4-(5-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (200 mg, 0.50 mmol) and 3-iodopyridine (410 mg, 2.0 mmol) in DMF (8 mL) was added (±)-trans-1,2-cyclohexanediamine (57 mg, 0.50 mmol), and K3PO4(320 mg, 1.5 mmol ) and CuI (96 mg, 0.50 mmol) and the mixture was stirred at 100 °C under N2overnight. It was then diluted with EtOAc and filtered. The filtrate was washed with LiCl (5% aq.) and brine, dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether, then 100% DCM) to provide tert-butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (170 mg, ~70% purity, 48%) as a light yellow solid. LC / MS ESI (m / z): 475 (M+H)+. Step 5.5-(2-Fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidine To tert-butyl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (170 mg, 0.24 mmol) in DCM (2 mL) was added HCl / dioxane (3.0 mL, 4.0 M). The mixture was stirred at rt overnight. The solvent was evaporated, the residue was diluted with DCM, washed with NaHCO3(aq.), brine, dried over Na2SO4and concentrated to provide 5-(2-fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidine (130 mg, 99%) as a solid. LC / MS ESI (m / z): 375 (M+H)+. Step 6.1-Fluoro-2-methylpropan-2-yl 4-(5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A mixture of 5-(2-fluorophenyl)-4-(piperazin-1-yl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidine (120 mg, 0.32 mmol), 1-fluoro-2-methylpropan-2-yl 1H-imidazole-1- carboxylate (180 mg, 0.97 mmol) and DIPEA (0.26 mL, 1.6 mmol) in DMF (5 mL) was stirred at 80 °C under N2for 40 h. The mixture was diluted with EtOAc, washed with LiCl (5% aq.), brine and was then concentrated. The residue was purified by flash column chromatography (silica gel, 0~50% EtOAc in petroleum ether) to give 80 mg of the crude product, which was further purified by prep-HPLC to afford 1-fluoro-2-methylpropan-2-yl 4- (5-(2-fluorophenyl)-7-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (38 mg, 24%) as a white solid. LC / MS ESI (m / z): 493 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.52 (s, 1H), 8.22 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.54 – 7.45 (m, 3H), 7.37 (tdd, J = 7.1, 5.1, 1.8 Hz, 1H), 7.28 – 7.19 (m, 2H), 4.45 (d, J = 47.5 Hz, 2H), 3.27 (d, J = 29.6 Hz, 8H), 1.45 (d, J = 2.2 Hz, 6H). The following compound was prepared by a synthetic procedure analogous to that described for compound 172, except using 5-iodopyrimidine in step 4.

[0011] Example 24. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (2R,5S)-4-(5-(2- fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (Compound 186) Step 1.1,1,1-Trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (500 mg, 3.9 mmol) in DCM (10 mL) was added di(1H-imidazol-1-yl)methanone (630 mg, 3.9 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with DCM twice, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated to afford 1,1,1-trifluoro-2-methylpropan-2-yl 1H- imidazole-1-carboxylate (640 mg, 73%) as a white solid. LC / MS ESI (m / z): 223 (M+H)+. Step 2.4-((2S,5R)-2,5-Dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (110 mg, 0.21 mmol, prepared following a similar procedure of compound 134 in DCM (2 mL) was added HCl / dioxane (0.50 mL, 4.0M). The resulting mixture was stirred at room temperature for 3h. After removal of solvent, the residue was dissolved in DCM, washed with NaHCO3(aq), the organic layer was separated, aqueous layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly.4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2- fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine. LC / MS ESI (m / z): 406 (M+H)+. Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1- methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1- carboxylate To a solution of 4-((2S,5R)-2,5-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)-7-(1- methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.074 mmol) in DMF (3 mL) was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (20 mg, 0.089 mmol) and DIPEA (0.040 mL, 0.22 mmol). The resulting mixture was stirred at 80oC for 2d under N2. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1,1,1- trifluoro-2-methylpropan-2-yl (2R,5S)-4-(5-(2-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (14 mg , 33%) as a white solid. LC / MS ESI (m / z): 560 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 0.5 Hz, 1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.26 – 7.16 (m, 2H), 4.27 – 4.03 (m, 2H), 4.00 (s, 3H), 3.39 (d, J = 13.1 Hz, 1H), 3.32 – 3.16 (m, 2H), 3.03 – 2.82 (m, 1H), 1.71 – 1.59 (m, 6H), 1.14 – 1.06 (m, 3H), 1.01 – 0.91 (m, 3H). The following compounds were prepared by the procedures analogous to the synthesis of compound 186 from the corresponding boronic acids and alcohols. Example 25. Synthesis of tert-butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 278) Compound 278Step 1. tert-Butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -3- methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 12 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.8 g, 29 mmol). The resulting mixture was heated to 140oC for 1.5 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (S)- 4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methyl piperazine-1-carboxylate (5.8 g, 84%) as a yellow solid. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolane -2-yl)- 7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), TEA (1.2 mL, 8.3 mmol), X-Phos (0.080 g, 0.16 mmol) and Pd2(dba)3(0.15 g, 0.16 mmol). The resulting mixture was stirred at 95oC overnight. After being cooled down to room temperature. The reaction was quenched with water, extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl (S)-3-methyl-4-(5- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate as a yellow oil, which was used in the next step directly. LC / MS ESI (m / z): 598 (M+H)+. Step 3. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo [2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H2O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K2CO3(1.2 g, 8.3 mmol) and Pd(dppf)Cl2(0.12 g, 0.16 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (0.69 g, 75%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 4. tert-Butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (690 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.0 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H- pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (450 mg, 90%) as a white solid. LC / MS ESI (m / z): 395 (M+H)+. Step 5. tert-Butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-3-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (120 mg, 0.30 mmol) in DMF (10 mL) were added 1-iodo-3-methoxybenzene (0.054 mL, 0.45 mmol), trans-cyclohexane-1,2-diamine (10 mg, 0.091 mmol), CuI (58 mg, 0.30 mmol) and K3PO4(190 mg, 0.91 mmol ). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3-methoxyphenyl)-5-(pyridin-2-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (13 mg, 8.0%) as a white solid. LC / MS ESI (m / z): 501 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.2 Hz, 1H), 8.42 (s, 1H), 8.04 (s, 1H), 7.94 (td, J = 7.7, 1.5 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 – 7.42 (m, 3H), 7.35 (dd, J = 7.0, 5.1 Hz, 1H), 7.05 – 6.92 (m, 1H), 4.18 (d, J = 5.9 Hz, 1H), 3.83 (s, 3H), 3.77 – 3.64 (m, 2H), 3.07 – 2.60 (m, 4H), 1.36 (s, 9H), 0.91 (d, J = 6.5 Hz, 3H). The following compound was prepared by an analogous procedure to the synthesis of compound 278 from the corresponding aryl halide. Example 26. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(1H-pyrazol-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 322) Step 1. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo [2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 13 mmol) in DIPEA (15 mL) was added tert-butyl (S)-3-methylpiperazine-1- carboxylate (6.4 g, 32 mmol). The resulting mixture was heated to 140oC for 2 h. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (5.9 g, 83%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H)+. Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(1H-pyrazol-1-yl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.36 mmol) in DMF (6 mL) were added 1H-pyrazole (49 mg, 0.72 mmol), Cs2CO3(470 mg, 1.4 mmol), Fe(acac)3(38 mg, 0.10 mmol) and Cu(acac)2(9.4 mg, 0.036 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(1H-pyrazol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (9.6 mg, 5.0 %) as a white solid. LC / MS ESI (m / z): 494 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.74 (t, J = 1.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.63 – 7.60 (m, 1H), 7.51 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.41 – 7.37 (m, 1H), 6.52 (t, J = 2.1 Hz, 1H), 4.24 – 3.79 (m, 2H), 3.67 (d, J = 12.8 Hz, 1H), 3.32 (m, 1H), 3.14 – 2.70 (m, 3H), 1.45 (s, 9H), 1.09 (s, 3H). The following compounds were prepared by analogous procedures to the synthesis of compound 322 from the corresponding amines. Example 27. Synthesis of tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 367) Step 1. tert-Butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) -2- methylpiperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.97 mL, 6.6 mmol), X-Phos (0.080 g, 0.16 mmol), TEA (1.2 mL, 8.3 mmol) and Pd2(dba)3(0.15 g, 0.16 mmol). The resulting mixture was stirred at 95oC overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude tert-butyl (R)-2-methyl-4- (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate as a yellow oil, which was used in the next step directly. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo [2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) in dioxane (15 mL) and H2O (3 mL) were added 2-bromopyridine (0.32 mL, 3.3 mmol), K2CO3(1.2 g, 8.3 mmol) and Pd(dppf)Cl2(0.12 g, 0.16 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (0.72 g, 78%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 3. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4- yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H- pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (720 mg, 1.3 mmol) in THF (5 mL) was added TBAF (5.2 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (510 mg, 98%) as a yellow solid. LC / MS ESI (m / z): 395 (M+H)+. Step 4. tert-Butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (510 mg, 1.2 mmol) in DMF(10 mL) were added 2-bromoisonicotinonitrile (470 mg, 2.5 mmol), CuI (250 mg, 1.2 mmol), trans-cyclohexane- 1,2-diamine (150 mg, 1.2 mmol) and K3PO4(820 mg, 3.8 mmol). The resulting mixture was heated to 120oC overnight. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(7-(4-cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2-methylpiperazine-1-carboxylate (600 mg, 93%) as a yellow solid.100 mg of the product was further purified by prep-HPLC to obtain 14.8 mg of the tert-butyl (R)-4-(7-(4- cyanopyridin-2-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1- carboxylate as a white solid. LC / MS ESI (m / z): 497 (M+H)+.1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.63 (dd, J = 5.0, 0.5 Hz, 1H), 8.59 – 8.53 (m, 2H), 7.85 – 7.79 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 5.0, 1.3 Hz, 1H), 7.34 – 7.29 (m, 1H), 4.24 – 4.19 (m, 1H), 3.84 (d, J = 12.9 Hz, 2H), 3.58 – 3.53 (m, 1H), 3.08 (dd, J = 13.2, 3.9 Hz, 1H), 2.89 – 2.83 (m, 2H), 1.43 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H). Example 28. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 400) Compound 400Step 1.4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine To a 0oC solution of formaldehyde (0.58 g, 7.1 mmol) in H2O (2 mL) and CH3COOH (10 mL, 86 mmol) and dioxane (10 mL). was added pyrrolidine (0.58 mL, 7.1 mmol), followed by a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) in dioxane dropwise. After being stirred at 50oC overnight under N2, the reaction was added to anhydrous sodium sulfate to dry and then filtered. The filtrate was concentrated at room temperature and purified by flash column chromatography (silica gel, 0~50%, methanol in dichloromethane) to afford 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (0.63 g, 40%) as a yellow oil. LC / MS ESI (m / z): 237 (M+H)+. Step 2.3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) benzonitrile To a solution of 4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (0.53 g, 2.2 mmol) in DCM (25 mL) were added (3-cyanophenyl)boronic acid (0.66 g, 4.4 mmol), Cu(OAc)2(1.2 g, 6.7 mmol), pyridine (1.1 mL, 13 mmol) and 4A molecular sieves (800 mg). The resulting mixture was stirred at room temperature under O2atmosphere overnight. The reaction was quenched with NH4OH (2 mL) at 0 ℃ and filtered. The filtrate was extracted with DCM twice and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, methanol in dichloromethane) to afford 3-(4-chloro-5-(pyrrolidin-1-ylmethyl)- 7H-pyrrolo [2,3-d]pyrimidin-7-yl)benzonitrile (0.26 g, 34%) as a yellow solid. LC / MS ESI (m / z): 338 (M+H)+. Step 3. tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo [2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 3-(4-chloro-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin- 7-yl)benzonitrile (100 mg, 0.29 mmol) in DIPEA (1 mL) was added tert-butyl (S)-3- methylpiperazine-1-carboxylate (240 mg, 1.1 mmol). The resulting mixture was heated to 140oC for 3 h. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, methanol in dichloromethane). The product was further purified by prep-HPLC to afford tert-butyl (S)-4- (7-(3-cyanophenyl)-5-(pyrrolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (75 mg, 50%) as a white solid. LC / MS ESI (m / z): 502 (M+H)+.1H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 8.24 (s, 1H), 8.13 – 8.03 (m, 1H), 7.77 – 7.69 (m, 2H), 7.65 (s, 1H), 4.52 (s, 1H), 4.06 – 3.91 (m, 2H), 3.90 – 3.65 (m, 3H), 3.58 – 3.40 (m, 2H), 3.27 – 3.10 (m, 1H), 2.71 – 2.58 (m, 4H), 1.86 – 1.74 (m, 4H), 1.50 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H).

[0012] Example 29. Synthesis of tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 402) pStep 1.5-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine At 0℃, to a solution of 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.7 mmol) in DMF(15 mL) was added NBS (0.95 g, 5.3 mmol) in portions. After being stirred at room temperature for 3 h under N2, the reaction was quenched with water. The reaction mixture was filtered to afford 5-bromo-4-methoxy-7H -pyrrolo[2,3-d]pyrimidine (0.45 g, 29%) as a yellow solid. LC / MS ESI (m / z): 228, 230 (M+H)+. Step 2.5-Bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine At 0℃, to a solution of 5-bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (450 mg, 1.9 mmol) in DMF (10 mg) was added NaH (95 mg, 2.3 mmol) in portions. The resulting mixture was stirred at 0℃ for 20 min. Then to above mixture was added 4- methylbenzenesulfonyl chloride (430 mg, 2.2 mmol) and the resulting mixture was stirred at 0℃ for 20 min and then was allowed to warm up to room temperature and stirred overnight under N2. The reaction was quenched with ice water. Then the reaction mixture was filtered to afford 5-bromo-4-methoxy-7-tosyl-7H-pyrrolo [2,3-d]pyrimidine (690 mg, 91%) as a gray solid. LC / MS ESI (m / z): 382,384 (M+H)+. Step 3.4-Methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of 5-bromo-4-methoxy-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (690 mg, 1.8 mmol) in dioxane (10 mL) and H2O (2 mL) were added 4,4,5,5-tetramethyl-2-(prop-1-en- 2-yl)-1,3,2-dioxaborolane (0.51 mL, 2.7 mmol), K2CO3(1000 mg, 7.2 mmol) and Pd(dppf)Cl2(130 mg, 0.18 mmol). The resulting mixture was heated to 90oC overnight. After being cooled down to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-methoxy-5-(prop-1-en-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (460 mg, 74%) as a white solid. LC / MS ESI (m / z): 344 (M+H)+. Step 4.4-Methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of Et2Zn (13 mL) in DCM (10 mL) at 0℃ was added dropwise a solution of TFA (0.50 mL, 6.6 mmol) in DCM (2 mL) and the mixture was stirred at 0℃ for 30 min. Then to the above mixture was added dropwise a solution of CH2I2(0.56 mL, 6.6 mmol) in DCM (2 mL). After being stirred for 20 min, a solution of 4-methoxy-5-(prop-1-en- 2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (460 mg, 1.3 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl (aq.), extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford 4-methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 73%) as a yellow oil. LC / MS ESI (m / z): 358 (M+H)+. Step 5.4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-methoxy-5-(1-methylcyclopropyl)-7-tosyl-7H- pyrrolo[2,3- d]pyrimidine (350 mg, 0.98 mmol) in THF (3 mL) was added TBAF (3.9 mL, 1.0M in THF). The resulting mixture was stirred at 30℃ for 4 h. The reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3- d]pyrimidine (40 mg, 20%) as a white solid. LC / MS ESI (m / z): 204 (M+H)+. Step 6.3-(4-Methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) benzonitrile To a solution of 4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.19 mmol) in DMF (5 mL) were added 3-iodobenzonitrile (180 mg, 0.78 mmol), CuI (37 mg, 0.19 mmol), trans-cyclohexane-1,2-diamine (45 mg, 0.39 mmol) and K3PO4 (130 mg, 0.59 mmol). The resulting mixture was heated to 100oC overnight. After being cooled down to room temperature, the reaction was quenched with water, extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 3-(4-methoxy-5-(1- methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) benzonitrile (55 mg, 91%) as a yellow solid. LC / MS ESI (m / z): 305 (M+H)+. Step 7.3-(4-Hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) benzonitrile To a solution of 3-(4-methoxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d] pyrimidin- 7-yl)benzonitrile (55 mg, 0.18 mmol) in DMF (2 mL) were added p-toluenesulfonic acid (310 mg, 1.8 mmol) and LiCl (77 mg, 1.8 mmol). The resulting mixture was heated to 110oC for 2 h. After being cooled down to room temperature, the reaction was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 3-(4-hydroxy-5-(1-methylcyclopropyl)-7H- pyrrolo[2,3-d] pyrimidin-7-yl) benzonitrile (50 mg, 95%) as a yellow solid. LC / MS ESI (m / z): 291 (M+H)+. Step 8.3-(4-Chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) benzonitrile The mixture of 3-(4-hydroxy-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d] pyrimidin- 7-yl)benzonitrile (50 mg, 0.17 mmol) and POCl3(5 mL) was heated to 120oC overnight. After being cooled down to room temperature, the reaction was concentrated. The residue was dissolved in DCM, washed with NaHCO3(aq.), and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 3-(4-chloro-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)benzonitrile (50 mg, 94%) as a yellow solid. LC / MS ESI (m / z): 309 (M+H)+. Step 9. tert-Butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)- 7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of 3-(4-chloro-5-(1-methylcyclopropyl)-7H-pyrrolo [2,3-d]pyrimidin-7- yl)benzonitrile (50 mg, 0.16 mmol) in DIPEA (1 mL) was added tert-butyl (S)-3- methylpiperazine-1-carboxylate (320 mg, 1.6 mmol). The resulting mixture was heated to 140oC for 6 h. After being cooled down to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give the product. Further purification by prep-HPLC provided tert-butyl (S)-4-(7-(3-cyanophenyl)-5-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (4.3 mg, 5.0%) as a white solid. LC / MS ESI (m / z): 473 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.38 – 8.30 (m, 1H), 8.27 – 8.18 (m, 1H), 8.08 – 8.01 (m, 1H), 7.73 – 7.66 (m, 2H), 7.47 – 7.42 (m, 1H), 4.97 – 4.86 (m, 1H), 4.07 (d, J = 12.9 Hz, 1H), 4.02 – 3.89 (m, 1H), 3.86 (d, J = 12.6 Hz, 1H), 3.61 – 3.36 (m, 2H), 3.25 – 3.05 (m, 1H), 1.54 (s, 3H), 1.50 (d, J = 5.9 Hz, 9H), 1.34 – 1.28 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H), 0.95 – 0.88 (m, 1H), 0.83 – 0.71 (m, 1H). The following compound was prepared by the procedure analogous to the synthesis of compound 402 from the corresponding aryl halide. Example 30. Synthesis of ethyl 4-(5-cyclopropyl-7-(5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 1004) Compound 1004 Step 1. Ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate A mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.2 mmol) and ethyl piperazine-1-carboxylate (220 mg, 1.4 mmol) was heated to 100oC overnight. After cooling down to room temperature, the reaction mixture was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (360 mg, 67%) as a white solid. LC / MS ESI (m / z): 470 (M+H)+. Step 2. Ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate To a solution of ethyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate (360 mg, 0.77 mmol) in THF (5 mL) was added TBAF (5.3 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg, 83%) as a yellow solid. LC / MS ESI (m / z): 316 (M+H)+. Step 3. Ethyl 4-(5-cyclopropyl-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of ethyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine- 1-carboxylate (100 mg, 0.32 mmol) in toluene (15 mL) were added 3-iodo-5- methoxypyridine (82 mg, 0.35 mmol), 1,10-phenanthroline (57 mg, 0.32 mmol), CuI (60 mg, 0.32 mmol) and Cs2CO3(310 mg, 0.95 mmol). The resulting mixture was heated to 110oC overnight. After cooling down to room temperature, the reaction was quenched with water, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl 4-(5-cyclopropyl-7-(5- methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (31 mg, 23%) as a white solid. LC / MS ESI (m / z): 423 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J = 2.6 Hz, 1H), 7.88 (t, J = 2.4 Hz, 1H), 7.59 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.66 – 3.62 (m, 4H), 3.62 – 3.57 (m, 4H), 2.09 – 2.01 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 – 0.97 (m, 2H), 0.88 – 0.83 (m, 2H). The following compounds were prepared by procedures analogous to the synthesis of compound 1004 using the corresponding amine. Example 31. Synthesis of ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 112) Step 1 (S)-7-(4-Chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (500 mg, 1.1 mmol, prepared following the procedures described for the synthesis of compound 114 in DCM (10 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO3(aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly. (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine (350 mg, 89% yield). LC / MS ESI (m / z): 368 (M+H)+. Step 2 Ethyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.25 mmol) in DCM (5 mL) at 0oC was added TEA (76 mg, 0.75 mmol), followed by ethyl carbonochloridate (54 mg, 0.50 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO3(aq.), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4-(7-(4- chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (34 mg, 31% yield) as a white solid. LC / MS ESI (m / z): 440 (M+H)+.1H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.62 – 7.58 (m, 2H), 7.48 – 7.44 (m, 2H), 6.90 (d, J = 0.7Hz, 1H), 4.81 – 4.70 (m, 1H), 4.24 – 4.17 (m, 2H), 4.16 – 4.01 (m, 1H), 4.00 – 3.81 (m, 2H), 3.65 – 3.51 (m, 1H), 3.44 – 3.30 (m, 1H), 3.28 – 3.13 (m, 1H), 2.04 (td, J = 8.0, 4.1Hz, 1H), 1.30 (t, J = 7.1Hz, 3H), 1.25 (d, J = 6.6Hz, 3H), 1.04 – 0.99 (m, 2H), 0.83 – 0.77 (m, 1H), 0.74 – 0.68 (m, 1H). Example 32. Synthesis of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 114) Compound 114Step 1.4-Chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 4.7 mmol) in DCM (50 mL) were added (4-chlorophenyl)boronic acid (1.5 g, 9.3 mmol), Cu(OAc)2(2.1 g, 12 mmol) and pyridine (2.2 mL, 28 mmol). The resulting mixture was stirred at room temperature overnight. NH3.H2O (30 mL) was added and the reaction was filtered. The filtrate was partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in petroleum ether) to afford 4-chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (810 mg, 45%) as a solid. LC / MS ESI (m / z): 390 (M+H)+. Step 2. tert-Butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 2.1 mmol) in DIPEA (5 mL) was added tert-butyl (S)-3-methylpiperazine-1- carboxylate (820 mg, 4.1 mmol). The resulting mixture was heated to 140oC for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert- butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (900 mg, 79%) as a white solid. LC / MS ESI (m / z): 554 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (S)-4-(7-(4-chlorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (900 mg, 1.6 mmol) in toluene (15 mL) were added cyclopropylboronic acid (280 mg, 0.16 mmol), K2CO3(2.9 g, 21 mmol) and Pd- 118 (100 mg, 1.3 mmol). The resulting mixture was heated to 80oC overnight. After cooling to room temperature, the reaction was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give tert-butyl (S)-4-(7-(4-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (580 mg, 76% yield) as a solid. LC / MS ESI (m / z): 468 (M+H)+.1H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.62 – 7.58 (m, 2H), 7.48 – 7.44 (m, 2H), 6.89 (s, 1H), 4.78 – 4.69 (m, 1H), 4.15 – 3.80 (m, 3H), 3.60 – 3.50 (m, 1H), 3.40 – 3.27 (m, 1H), 3.22 – 3.05 (m, 1H), 2.07 – 2.00 (m, 1H), 1.50 (s, 9H), 1.24 (d, J = 6.6Hz , 3H), 1.04 – 0.99 (m, 2H), 0.82 – 0.76 (m, 1H), 0.73 – 0.67 (m, 1H). The following compounds were prepared by procedures analogous to the synthesis of compound 114 using the corresponding boronic acids and amine. Example 33. Synthesis of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 119) Step 1. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.7 mmol, prepared following step 1 of the procedures described for compound 274), tert- butyl (S)-3-methylpiperazine-1-carboxylate (3.1 g, 15 mmol) in DIEA (20 mL) was heated at 150°C for 6 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~30% ethyl acetate in petroleum ether) to give tert- butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (3.5 g, 6.2 mmol, 81%) as a yellow solid. LC / MS ESI (m / z): 554 (M+H)+. Step 2. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (3.5 g, 6.2 mmol), 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3.6 mL, 25 mmol), Pd2(dba)3(0.60 g, 0.62 mmol), X-Phos (0.60 g, 1.3 mmol) and TEA (4.3 mL, 31 mmol) in dioxane (60 mL) was heated at 95°C for 12 hours. The reaction mixture was filtered. The filtrate was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was used in the next step directly. LC / MS ESI (m / z): 554 (M+H)+. Step 3. tert-Butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (1.0 g, 1.8 mmol), 2-bromopyridine (0.35 mL, 3.6 mmol), Pd(dppf)Cl2(130 mg, 0.18 mmol) and K2CO3(1.3 g, 9.0 mmol) in dioxane (20 mL) and H2O (2 mL) was stirred at 90°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give the crude product. The crude product was purified by prep-HPLC to give the tert-butyl (S)-4-(7-(3- chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1- carboxylate (300 mg, 33%) as a white solid. LC / MS ESI (m / z): 505 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.2 Hz, 1H), 8.53 (s, 1H), 7.82 – 7.76 (m, 2H), 7.69 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.29 – 7.24 (m, 1H), 4.40 – 4.16 (m, 1H), 4.03 – 3.76 (m, 1H), 3.58 (t, J = 15.4 Hz, 2H), 3.17 (t, J = 11.8 Hz, 1H), 3.06 – 2.71 (m, 2H), 1.44 (s, 9H), 1.04 (br. s, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 119 using the corresponding aryl halides. Example 34. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)- 5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 121) Step 1. (S)-7-(3-Chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (200 mg, 0.40 mmol, prepared following the procedures described for compound 119 in DCM (10 mL) was added TFA (5.0 mL, 67 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basified with NaHCO3(aq.) to pH 8 and then extracted with DCM (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated to afford (S)-7-(3-chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidine (170 mg, 94%) as a yellow solid which was used in the next step directly without further purification. LC / MS ESI (m / z): 405 (M+H)+. Step 2.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-(pyridin-2- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of (S)-7-(3-chlorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidine (170 mg, 0.41 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl 1H- imidazole-1-carboxylate (110 mg, 0.50 mmol) and DIEA (0.20 mL, 1.2 mmol) in DMF (10 mL) was stirred at 80°C for 24 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~50% ethyl acetate in petroleum ether) to give the crude product. The crude product was purified by prep-HPLC to give the 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (54 mg, 24%) as a white solid. LC / MS ESI (m / z): 559 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.70 – 8.68 (m, 1H), 8.45 (s, 1H), 8.01 (td, J = 7.8, 1.7 Hz, 1H), 7.96 (t, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.78 – 7.73 (m, 2H), 7.58 (t, J = 8.1 Hz, 1H), 7.49 – 7.43 (m, 2H), 4.26 (d, J = 6.4 Hz, 1H), 3.82 (dd, J = 44.3, 12.4 Hz, 1H), 3.58 (dd, J = 32.0, 12.9 Hz, 2H), 3.17 (td, J = 13.1, 3.2 Hz, 1H), 3.07 – 2.81 (m, 2H), 1.67 (s, 6H), 1.02 (d, J = 6.6 Hz, 3H). Example 35. Synthesis of tert-butyl (R)-4-(7-(3-chloro-5-fluorophenyl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 123) Step 1. tert-Butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.87 mmol, prepared following step 2 of the procedures described for compound 164 in EtOH (5 mL) were added tert-butyl (R)-2-methylpiperazine-1-carboxylate (350 mg, 1.7 mmol) and DIPEA (670 mg, 5.2 mmol). The resulting mixture was heated to 100oC overnight. After cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (300 mg, 73%) as a white solid. LC / MS ESI (m / z): 512 (M+H)+. Step 2. tert-Butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.60 mmol) in THF (5 mL) was added TBAF (3.6 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (190 mg, 88%) as a white solid. LC / MS ESI (m / z): 358 (M+H)+. Step 3. tert-Butyl (R)-4-(7-(3-chloro-5-fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (3S)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperidine-4-carboxylate (80 mg, 0.23 mmol) in DMF (5 mL) were added 1-chloro-3- fluoro-5-iodobenzene (120 mg, 0.46 mmol), trans-cyclohexane-1,2-diamine (7.9 mg, 0.070 mmol), CuI (13 mg, 0.070 mmol) and K3PO4(150 mg, 0.69 mmol). The resulting mixture was heated to 100oC overnight. After cooling to room temperature, the reaction was quenched with water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-4-(7-(3-chloro-5- fluorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1- carboxylate (61 mg, 56%) as a solid. LC / MS ESI (m / z): 486 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.77 (s, 1H), 7.69 – 7.62 (m, 1H), 7.33 (s, 1H), 7.23 – 7.18 (m, 1H), 4.51 (d, J = 12.7 Hz, 1H), 4.43 (s, 1H), 4.13 (d, J = 13.1 Hz, 1H), 3.96 (d, J = 13.3 Hz, 1H), 3.49 – 3.36 (m, 2H), 3.15 – 3.06 (m, 1H), 2.13 – 2.02 (m, 1H), 1.51 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.10 – 1.04 (m, 2H), 1.02 – 0.96 (m, 1H), 0.76 – 0.69 (m, 1H). The following compound was prepared by procedures analogous to the synthesis of compound 123 using the corresponding amines and aryl halides. Example 36. Synthesis of ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 126) Compound 126Step 1. (S)-5-(2-Fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2-methylpiperazin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol, prepared following an analogous procedure described for compound 1004 in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 0.5h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO3(aq.). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly. (S)-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)- 4-(2-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 63%). LC / MS ESI (m / z): 419 (M+H)+. Step 2. Ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-4-(2- methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.10 mmol) in DCM (3 mL) at 0oC was added TEA (0.30 mL, 0.30 mmol), followed by ethyl carbonochloridate (0.020 mL, 0.20 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO3(aq.), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4-(5-(2-fluorophenyl)-7-(5-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3-methylpiperazine-1-carboxylate (31 mg, 63%) as a white solid. LC / MS ESI (m / z): 491 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.94 (t, J = 2.3 Hz, 1H), 7.56 (td, J = 7.5, 1.5 Hz, 1H), 7.50 – 7.45 (m, 1H), 7.40 – 7.35 (m, 2H), 4.19 – 4.14 (m, 1H), 4.04 – 3.98 (m, 2H), 3.92 (s, 3H), 3.66 – 3.60 (m, 1H), 3.50 – 3.41 (m, 3H), 3.03 – 2.96 (m, 1H), 2.74 – 2.68 (m, 1H), 1.14 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H). Example 37. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)- 5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 140) Compound 140Step 1.2,2,2-Trifluoroethyl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (1.0 g, 0.78 mmol) in DCM (10 mL) was added CDI (1.4 g, 0.86 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.1 g, 64%) as a white solid. LC / MS ESI (m / z): 223 (M+H)+. Step 2.1,1,1-Trifluoro-2-methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(4-chlorophenyl)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.19 mmol, prepared following the procedures described for compound 461) in DMF (5 mL) were added 1,1,1-trifluoro-2-methylpropan-2- yl 1H-imidazole-1-carboxylate (84 mg, 0.38 mmol) and DIPEA (74 mg, 0.57 mmol). The resulting mixture was stirred at 80oC overnight under a N2atmosphere. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford 1,1,1-trifluoro-2- methylpropan-2-yl (S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylpiperazine-1-carboxylate (29 mg, 29% yield) as a white solid. LC / MS ESI (m / z): 522 (M+H)+.1H NMR (400 MHz, CDCl3) δ8.45 (s, 1H), 7.68 (t, J = 2.0Hz, 1H), 7.62 – 7.57 (m, 1H), 7.42 (t, J = 8.1Hz, 1H), 7.33 – 7.29 (m, 1H), 6.93 (s, 1H), 4.79 – 4.71 (m, 1H), 4.15 – 3.79 (m, 3H), 3.57 (t, J = 12.6Hz, 1H), 3.43 – 3.32 (m, 1H), 3.30 – 3.11 (m, 1H), 2.08 – 2.00 (m, 1H), 1.73 (d, J = 7.2Hz, 6H), 1.24 (d, J = 6.6Hz, 3H), 1.05 – 0.99 (m, 2H), 0.84 – 0.77 (m, 1H), 0.75 – 0.68 (m, 1H). The following compounds were prepared by a procedure analogous to the synthesis of compound 140 from the corresponding amines. Example 38. Synthesis of ethyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 153) Step 1. (S)-5-Cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (80 mg, 0.16 mmol, prepared following an analogous procedure described for compound 259) in DCM (3 mL) was added HCl (4.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 0.5h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO3(aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly. (S)-5-cyclopropyl-4-(2- methylpiperazin-1-yl)-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 63%). LC / MS ESI (m / z): 349 (M+H)+. Step 2. Ethyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-5-cyclopropyl-4-(2-methylpiperazin-1-yl)-7-(5-methylpyridin-3- yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.10 mmol) in DCM (3 mL) at 0oC was added TEA (0.30 mL, 0.30 mmol), followed by ethyl carbonochloridate (0.020 mL, 0.20 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO3(aq.), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4- (5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (31 mg, 63%) as a white solid. LC / MS ESI (m / z): 421 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 1.1 Hz, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.54 (s, 1H), 4.74 – 4.67 (m, 1H), 4.14 – 4.07 (m, 2H), 4.03 – 3.91 (m, 2H), 3.81 (d, J = 12.9 Hz, 1H), 3.50 – 3.39 (m, 2H), 3.18 – 3.11 (m, 1H), 2.39 (s, 3H), 2.06 – 2.00 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.01 – 0.96 (m, 2H), 0.90 – 0.86 (m, 1H), 0.81 – 0.77 (m, 1H). Example 39. Synthesis of ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 155) pStep 1. (S)-7-(3-Chloro-4-fluorophenyl)-4-(2-methylpiperazin-1-yl)-5-(pyridin-2-yl)- 7H-pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (400 mg, 0.77 mmol, prepared following the procedures described for compound 154 in DCM (5 mL) was added HCl (3.0 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 2 h. After removal of solvent, the residue was diluted with DCM and washed with NaHCO3(aq.). The organic layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was used in the next step directly. (S)-7-(3-chloro-4-fluorophenyl)-4-(2-methylpiperazin-1- yl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (280 mg). LC / MS ESI (m / z): 423 (M+H)+. Step 2. Ethyl (S)-4-(7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of (S)-7-(3-chloro-4-fluorophenyl)-4-(2-methylpiperazin-1-yl)-5- (pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (97 mg, 0.23 mmol) in DCM (5 mL) at 0oC was added TEA (70 mg, 0.69 mmol), followed by ethyl carbonochloridate (75 mg, 0.69 mmol) dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with NaHCO3(aq), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford ethyl (S)-4- (7-(3-chloro-4-fluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (41 mg, 36%) as a white solid. LC / MS ESI (m / z): 495 (M+H)+.1H NMR (400MHz, CDCl3) δ8.69 (d, J = 4.1Hz, 1H), 8.52 (s, 1H), 7.85 (dd, J = 6.4 , 2.6Hz, 1H), 7.79 (td, J = 7.7 , 1.8Hz, 1H), 7.67 – 7.63 (m, 2H), 7.59 (d, J = 7.8Hz, 1H), 7.31 (t, J = 8.7Hz, 1H), 7.28 – 7.24 (m, 1H), 4.39 – 4.23 (m, 1H), 4.16 – 4.08 (m, 2H), 3.98 – 3.83 (m, 1H), 3.62 (dd, J = 26.8 , 12.6Hz, 2H), 3.22 – 3.13 (m, 1H), 3.09 – 2.79 (m, 2H), 1.24 (t, J = 7.1Hz, 3H), 1.05 (d, J = 6.3Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 155 from the corresponding Boc-protected amines. Example 40. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 157) Step 1.4-Chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3- d]pyrimidine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.6 mmol, prepared following step 1 of the procedures described for compound 274) in dioxane-H2O (15 mL, 5:1 v / v) were added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (450 mg, 2.3 mmol), K2CO3(1.1 g, 7.8 mmol) and Pd(dppf)Cl2(190 mg, 0.26 mmol). The resulting mixture was heated to 90oC overnight. After cooling to room temperature, the reaction was filtered and the filtrate was partitioned between EtOAc and waterThe aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in petroleum ether) to give 300 mg of 4- chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (36% yield) as a solid. LC / MS ESI (m / z): 330 (M+H)+. Step 2. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of 4-chloro-7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3- d]pyrimidine (100 mg, 0.30 mmol) and tert-butyl (R)-3-methylpiperazine-1-carboxylate (120 mg, 0.60 mmol) in DIPEA (0.5 mL) was stirred at 140oC for 3 h. After cooling to room temperature, the DIPEA was removed by vacuum. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in petroleum ether) to afford tert-butyl (R)-4-(7- (3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (110 mg, 73%) as a white solid. LC / MS ESI (m / z): 494 (M+H)+. Step 3. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate A mixture of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(cyclopent-1-en-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (110 mg, 0.22 mmol ), PtO2(51 mg) in EtOAc (8 mL) was stirred at room temperature for overnight under H2atmosphere (~1 atm).The reaction was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in petroleum ether) and prep- HPLC to give tert-butyl (R)-4-(7-(3-chlorophenyl)-5-cyclopentyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (38 mg, 35% yield) as a white solid. LCMS ESI (m / z): 496. (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 4.18 (s, 1H), 3.91 (s, 1H), 3.65 (s, 1H), 3.48 (s, 3H), 3.33 – 3.19 (m, 2H), 2.28 (s, 1H), 2.15 (s, 1H), 1.90 – 1.63 (m, 6H), 1.50 (s, 9H), 1.18 (d, J = 6.1 Hz, 3H). The following compound was prepared by procedures analogous to the synthesis of compound 157 from the corresponding amine. Example 41. Synthesis of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (Compound 169) Compound 169Step 1.4-Chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a suspension of NaH (1.0 g, 27 mmol, 60% wt%) in anhydrous DMF (60 mL) at 0oC was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 18 mmol) in portions. The resulting mixture was stirred at 0oC for 30 minutes before TosCl (3.4 g, 18 mmol) was added in portions. After the addition, the reaction was stirred at room temperature overnight. The reaction was poured into ice water, filtered. The solid was collected and further dried in vacuo to give 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 77%) as a white solid. LCMS ESI (m / z): 434 (M+H)+. Step 2. tert-Butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 9.2 mmol) in DIPEA (5.0 mL, 28 mmol) was added tert-butyl (2R,5S)-2,5-dimethylpiperazine-1- carboxylate (2.0 g, 9.2 mmol). The resulting mixture was heated to 150oC for 3 h under a N2atmosphere. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (2.5 g, 43%) as a yellow solid. LC / MS ESI (m / z): 612 (M+H)+. Step 3. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.30 mmol) in dioxane (10 mL) and H2O (1 mL) were added phenylboronic acid (60 mg, 0.60 mmol), K2CO3(100 mg, 0.75 mmol) and Pd(dppf)Cl2(18 mg, 0.010 mmol). The resulting mixture was stirred at 90oC overnight under a N2atmosphere. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 72%) as a yellow solid. LC / MS ESI (m / z): 562 (M+H)+. Step 4. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (100 mg, 0.18 mmol) in THF (2 mL) was added TBAF (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (50 mg, 69%) as a white solid. LC / MS ESI (m / z): 408 (M+H)+. Step 5. tert-Butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 0.12 mmol) in DMF (10 mL) were added 3-iodopyridine (50 mg, 0.24 mmol), trans-cyclohexane-1,2-diamine (15 mg, 0.12 mmol), CuI (25 mg, 0.12 mmol) and K3PO4(280 mg, 1.2 mmol). The resulting mixture was heated to 100oC overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (2R,5S)-2,5-dimethyl-4-(5-phenyl-7-(pyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (50 mg, 85%) as a white solid, which was further purified by prep-HPLC to afford 29 mg of white solid. LC / MS ESI (m / z): 485 (M+H)+.1H NMR (400 MHz, MeOD) δ 9.09 (s, 1H), 8.58 (d, J = 4.3 Hz, 1H), 8.41 (s, 1H), 8.33 (ddd, J = 8.3, 2.5, 1.4 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J = 8.3, 4.8 Hz, 1H), 7.61 – 7.58 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 4.24 – 4.10 (m, 2H), 3.47 – 3.42 (m, 1H), 3.29 – 3.21 (m, 2H), 2.97 – 2.80 (m, 1H), 1.43 (s, 9H), 1.14 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). Example 42. Synthesis of tert-butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 174) and tert-butyl (R)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2-methylpiperazine-1-carboxylate (Compound 175) Compound 174 Compound 175Step 1. tert-Butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate A mixture of 4-chloro-5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (350 mg, 1.0 mmol, prepared following the procedures described for compound 164, tert-butyl 2- methylpiperazine-1-carboxylate (240 mg, 1.2 mmol) and DIEA (0.50 mL, 3.0 mmol) in EtOH (10 mL) was stirred at 100°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~40% EtOAc in petroleum ether) to give the tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (390 mg, 0.76 mmol, 76%) as a yellow solid. LC / MS ESI (m / z):512 (M+H)+. Step 2. tert-Butyl 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-2-methylpiperazine-1-carboxylate (390 mg, 0.76 mmol) in THF (20 mL) was added TBAF (4.6 mL, 1.0M in THF) dropwise. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with EtOAc (100 mL x2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (0~80% EtOAc in petroleum ether) to give the tert-butyl 4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2- methylpiperazine-1-carboxylate (220 mg, 0.62 mmol, 81%) as a white solid. LC / MS ESI (m / z): 358 (M+H)+. Step 3. tert-Butyl (S)-4-(5-cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate and tert-butyl (R)-4-(5-cyclopropyl-7-(5- methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate A mixture of tert-butyl 4-{5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2- methylpiperazine-1-carboxylate (220 mg, 0.62 mmol), 3-bromo-5-methylpyridine (210 mg, 1.2 mmol), copper (I) iodide (35 mg, 0.18 mmol ), trans-1,2-diaminocyclohexane (21 mg, 0.18 mmol) and K3PO4(391 mg, 1.8 mmol) in DMF (20 mL) was stirred at 120°C for 16 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~30% EtOAc in petroleum ether) to give the tert-butyl 4-[5- cyclopropyl-7-(5-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylpiperazine- 1-carboxylate (120 mg, 0.27 mmol, 44%), which was separated by SFC to afford the two isomers: Peak 1 (shorter retention time): Assigned as tert-butyl (S)-4-(5-cyclopropyl-7-(5- methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (39 mg) as a light yellow solid. LC / MS ESI (m / z): 449 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.3 Hz, 1H), 8.44 – 8.40 (m, 2H), 7.93 (s, 1H), 6.95 (d, J = 0.8 Hz, 1H), 4.53 – 4.47 (m, 1H), 4.41 (s, 1H), 4.11 (d, J = 12.9 Hz, 1H), 3.97 (d, J = 13.1 Hz, 1H), 3.44 – 3.32 (m, 2H), 3.09 (td, J = 12.4, 3.4 Hz, 1H), 2.45 (s, 3H), 2.08 – 2.01 (m, 1H), 1.50 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.03 (dd, J = 8.3, 3.9 Hz, 2H), 0.91 – 0.86 (m, 1H), 0.70 – 0.65 (m, 1H). Peak 2 (longer retention time): Assigned as tert-butyl (R)-4-(5-cyclopropyl-7-(5- methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (44 mg) as a light yellow solid. LC / MS ESI (m / z): 449 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 5.8 Hz, 2H), 7.93 (s, 1H), 6.95 (d, J = 0.8 Hz, 1H), 4.55 – 4.46 (m, 1H), 4.41 (s, 1H), 4.11 (d, J = 13.0 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.44 – 3.31 (m, 2H), 3.09 (td, J = 12.4, 3.4 Hz, 1H), 2.45 (s, 3H), 2.09 – 1.97 (m, 1H), 1.50 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.07 – 1.02 (m, 2H), 0.91 – 0.86 (m, 1H), 0.70 – 0.65 (m, 1H). SFC Preparative separation method: Instrument: Waters Thar 80 preparative SFC ; Column: ChiralPak IC, 250×21.2 mm I.D, 5 µm; Mobile phase: A for CO2and B for MeOH+0.1% NH3·H2O; Gradient: B 40%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm ; Cycle-time: 5.0 min; Elution time: 4 h. Example 43. Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl(S)-3-methyl-4-(7-(1- methyl-1H-pyrazol-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate (Compound 183) Step 1.1,1,1-Trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate To a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (200 mg, 1.6 mmol) in DCM (5.0 mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (250 mg, 1.6 mmol) at room temperature. The resulting mixture was stirred for 18h. The reaction was quenched with water. The aqueous layer was extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was used in the next step directly. LC / MS ESI (m / z): 223 (M+H)+Step 2. (S)-7-(1-Methyl-1H-pyrazol-4-yl)-4-(2-methylpiperazin-1-yl)-5-phenyl-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl(3S)-3-methyl-4-[7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate (120 mg, 0.25 mmol, prepared following an analogous procedure described for compound 268) in DCM (5 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 18h. The mixture was concentrated. The residue was neutralized by addition of saturated Na2CO3solution and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was used directly without further purification. LC / MS ESI (m / z): 374 (M+H)+Step 3.1,1,1-Trifluoro-2-methylpropan-2-yl(S)-3-methyl-4-(7-(1-methyl-1H-pyrazol- 4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A solution of (2S)-2-methyl-1-[7-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl]piperazine (50 mg, 0.13 mmol), 1,1,1-trifluoro-2-methylpropan- 2-yl-1H-imidazole-1-carboxylate (49 mg, 0.22 mmol) and DIEA (0.050 mL, 0.33 mmol) in DMF (3 mL) was stirred at 80℃ for 2 days, then the mixture was cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted twice by EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtOAc in petroleum ether, 1:100 to 1:5 v / v) and prep-HPLC to give 1,1,1-trifluoro-2-methylpropan-2-yl (S)-3-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)-5- phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (5.3 mg, 7.5%) as a white solid. LC / MS ESI (m / z): 528 (M+H)+ 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.58 – 7.52 (m, 3H), 7.48 (dd, J = 14.1, 6.2 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 4.14 (dd, J = 6.5, 4.0 Hz, 1H), 3.98 (s, 3H), 3.86 – 3.68 (m, 1H), 3.56 (d, J = 13.2 Hz, 1H), 3.41 (dd, J = 23.2, 14.2 Hz, 1H), 3.18 – 3.10 (m, 1H), 2.85 (dd, J = 48.9, 12.1 Hz, 2H), 1.64 (s, 6H), 0.91 (d, J = 6.7 Hz, 3H). Example 44. Synthesis of tert-butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H- pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 187) Step 1. tert-Butyl 4-(1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4- yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl 4-(3-bromo-1-(3-chlorophenyl)-1H-pyrrolo[3,2-c]pyridin- 4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.12 mmol, prepared following the procedures of the first two steps of compound 418 synthesis) in toluene (5 mL) were added 2- (tributylstannyl)pyridine (0.050 mL, 0.14 mmol) and Pd(PPh3)4(14 mg, 0.012 mmol). The resulting mixture was stirred at 120oC overnight. After cooling to room temperature, the reaction was quenched with KF (aq.) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl 4- (1-(3-chlorophenyl)-3-(pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-3-methylpiperazine-1- carboxylate (8.4 mg, 14%) as a white solid. LC / MS ESI (m / z): 504 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 4.7 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.78 – 7.75 (m, 1H), 7.69 – 7.67 (m, 1H), 7.64 – 7.55 (m, 2H), 7.51 (dt, J = 7.5, 1.8 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.26 (d, J = 6.0 Hz, 1H), 3.56 – 3.42 (m, 2H), 3.24 – 3.07 (m, 4H), 2.88 – 2.73 (m, 1H), 1.43 (s, 9H), 0.84 (d, J = 6.5 Hz, 3H). The following compound was prepared by a procedure analogous to the synthesis of compound 187 using the corresponding tin reagent. Example 45. Synthesis of ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (Compound 189) Compound 189Step 1.4-Chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.3 mmol, prepared following the procedures described for compound 274), cyclopropylboronic acid (110 mg, 1.3 mmol), Pd(dtbpf)Cl2(170 mg, 0.26 mmol) and K2CO3(3.6 g, 26 mmol) in toluene (20 ml) was heated at 80°C for 12 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (0~40% EtOAc in petroleum ether) to give the 4-chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidine (300 mg, 77%) as a yellow solid. LC / MS ESI (m / z): 304 (M+H)+. Step 2.7-(3-Chlorophenyl)-5-cyclopropyl-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidine (300 mg, 1.0 mmol) and TBAF (2.0 ml, 1.0M in THF) in DMSO (20 mL) was stirred at 50°C for 3 hours. The resulting mixture was quenched with ice water and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (0~30% EtOAc in petroleum ether) to give 7-(3-chlorophenyl)-5-cyclopropyl-4-fluoro-7H- pyrrolo[2,3-d]pyrimidine (120 mg, 42%) as a white solid. LC / MS ESI (m / z): 288 (M+H)+. Step 3. tert-Butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate A mixture of 7-(3-chlorophenyl)-5-cyclopropyl-4-fluoro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.35 mmol), tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (150 mg, 0.70 mmol) and DIEA (0.17 mL, 1.1 mmol) in DMSO (10 mL) was stirred at 150°C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned, between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30% ethyl acetate in petroleum ether) to afford the tert-butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,5-dimethylpiperazine-1-carboxylate (60 mg, 35%). LC / MS ESI (m / z): 482 (M+H)+. Step 4.7-(3-Chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine To a solution of tert-butyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (60 mg, 0.13 mmol) in DCM (10 mL) was added HCl (3.0 mL, 4.0M in dioxane). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to afford 7-(3- chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin-1-yl)-7H-pyrrolo[2,3- d]pyrimidine (48 mg, 100%) as a yellow solid which was used in the next step directly without further purification. LC / MS ESI (m / z): 382 (M+H)+. Step 5. Ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5-cyclopropyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate To a mixture of 7-(3-chlorophenyl)-5-cyclopropyl-4-((2S,6S)-2,6-dimethylpiperazin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.11 mmol) and DIEA (0.050 mL, 0.31 mmol) in DCM (10 mL) at 0 °C was added ethyl carbonochloridate (14 mg, 0.13 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NaHCO3(aq.), extracted with DCM (50 ml x 2). The organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography on silica gel (0~50% EtOAc in petroleum ether) to give the crude product. The crude product was purified by HPLC to afford the ethyl (3S,5S)-4-(7-(3-chlorophenyl)-5- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate (15 mg, 0.033 mmol, 32%) 1006as a white solid. LC / MS ESI (m / z): 454 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.30 (s, 1H), 4.23 – 4.11 (m, 4H), 3.82 (s, 2H), 3.45 (s, 2H), 2.37 – 2.29 (m, 1H), 1.30 (t, J = 5.4 Hz, 6H), 1.06 (d, J = 6.3 Hz, 5H), 0.96 – 0.85 (m, 1H), 0.64 – 0.56 (m, 1H). Example 46. Synthesis of tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 193) Compound 193Step 1.4-Chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10 g, 36 mmol) in DCM (600 mL) were added (3-chlorophenyl)boronic acid (11 g, 72 mmol), Cu(OAc)2(16 g, 110 mmol), pyridine (18 mL, 110 mmol) and 4A molecular sieves (10 g). The resulting mixture was stirred at room temperature under an O2atmosphere for 3 days. After cooling with an ice-water bath, the reaction was quenched with NH4OH (aq. solution, 50 mL) and filtered. The filtrate was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 4-chloro-7-(3-chlorophenyl)-5- iodo-7H-pyrrolo[2,3-d]pyrimidine (11 g, 79%) as a white solid. LC / MS ESI (m / z): 390 (M+H)+. Step 2.7-(3-Chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of 4-chloro-7-(3-chlorophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 10 mmol) in MeOH (40 mL) was added MeONa (8.0 mL, 4.5M in MeOH). The resulting mixture was stirred at 50oC overnight. The reaction was quenched with ice water, extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford 7-(3-chlorophenyl)-5-iodo-4- methoxy-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 79%) as a white solid. LC / MS ESI (m / z): 386 (M+H)+. Step 3.7-(3-Chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidine To a solution of 7-(3-chlorophenyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (2.3 g, 6 mmol) in DMSO (20 mL) were added CuI (230 mg, 1.2 mmol), K2CO3(2.5 g, 18 mmol), L- proline (280 mg, 2.4 mmol) and pyrrolidine (850 mg, 12 mmol). The resulting mixture was heated at 90oC overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford 7-(3-chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H- pyrrolo[2,3-d]pyrimidine (1.2 g, 61%) as a yellow solid. LC / MS ESI (m / z): 329 (M+H)+. Step 4.7-(3-Chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol A solution of 7-(3-chlorophenyl)-4-methoxy-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidine (0.50 g, 1.5 mmol) in DCM (10 mL) was treated with BBr3(3.0 mL) dropwise at 0oC. The resulting mixture was stirred at 0oC for 2 h. The reaction was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford 7-(3- chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.40 g, 84%) as a yellow solid. LC / MS ESI (m / z): 315 (M+H)+. Step 5.4-Chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine A solution of 7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.40 g, 1.2 mmol) in POCl3(4 mL) was heated at 120oC overnight. After cooling to room temperature, the reaction was concentrated. The residue was re-dissolved in DCM and washed with NaHCO3(aq.). The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to afford 4-chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)- 7H-pyrrolo[2,3-d]pyrimidine (0.20 g, 48%) as a yellow solid. LC / MS ESI (m / z): 333 (M+H)+. Step 6. tert-Butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of 4-chloro-7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidine (200 mg, 0.60 mmol) in EtOH (5 mL) were added DIPEA (230 mg, 1.8 mmol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate (240 mg, 1.2 mmol). The resulting mixture was heated at 100oC overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~40%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (R)-4-(7-(3-chlorophenyl)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (36 mg, 12%) as a yellow solid. LC / MS ESI (m / z): 497 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.03 (s, 1H), 4.84 – 4.78 (m, 2H), 4.50 – 4.45 (m, 1H), 4.37 – 4.31 (m, 1H), 3.92 – 3.86 (m, 1H), 3.40 – 3.33 (m, 1H), 3.28 – 3.25 (m, 2H), 3.00 (td, J = 12.5, 3.6 Hz, 1H), 2.89 – 2.84 (m, 2H), 2.03 – 1.98 (m, 4H), 1.48 (s, 9H), 1.08 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 193 using the corresponding boronic acids and amines. In cases involving tert- butyl (S)-3-methylpiperazine-1-carboxylate or tert-butyl (R)-3-methylpiperazine-1- carboxylate in the last step, 5 eq. of the amine was used, and the reaction was run at 140oC.

[0013] Example 47. Synthesis of tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 211) Step 1. tert-Butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of 4-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (12 g, 28 mmol, prepared following step 1 of the procedures described for compound 192 in DIPEA (100 mL) was added tert-butyl (R)-3-methylpiperazine-1-carboxylate (11 g, 55 mmol). The resulting mixture was heated to 150oC for 3 h. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-iodo-7-tosyl-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (11 g, 66%) as a white solid. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (3.5 g, 5.9 mmol) in toluene (30 mL) were added cyclopropylboronic acid (1.0 g, 12 mmol), K2CO3(11 g, 77 mmol) and Pd-118 (390 mg, 0.59 mmol). The resulting mixture was heated to 80oC overnight. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.9 g, 63%) as a white solid. LC / MS ESI (m / z): 512 (M+H)+. Step 3. tert-Butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-3-methylpiperazine-1-carboxylate (1.9 g, 3.7 mmol) in THF (30 mL) was added TBAF (22 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~60%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate (1.1 g, 83%) as white solid. LC / MS ESI (m / z): 358 (M+H)+. Step 4. tert-Butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3- methylpiperazine-1-carboxylate(100 mg, 0.28 mmol) in DMF (10 mL) were added 1,3- difluoro-5-iodobenzene (130 mg, 0.56 mmol), trans-cyclohexane-1,2-diamine (9.7 mg, 0.084 mmol), CuI (27 mg, 0.15 mmol) and K3PO4(180 mg, 0.84 mmol). The resulting mixture was heated to 120oC overnight. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep- HPLC to afford tert-butyl (R)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (44 mg, 33%) as a white solid. LC / MS ESI (m / z): 470 (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.57 – 7.51 (m, 2H), 7.29 (d, J = 0.6 Hz, 1H), 6.97 – 6.89 (m, 1H), 4.75 (s, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.86 (d, J = 12.7 Hz, 2H), 3.59 – 3.34 (m, 2H), 3.24 – 3.07 (m, 1H), 2.10 – 2.02 (m, 1H), 1.50 (s, 9H), 1.20 (d, J = 6.6 Hz, 3H), 1.07 – 1.01 (m, 2H), 0.91 – 0.86 (m, 1H), 0.80 – 0.72 (m, 1H). The following compounds were prepared by procedures analogous to the synthesis of compound 211 from the corresponding aryl halides. Example 48. Synthesis of tert-butyl (R)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (Compound 215) Step 1. tert-Butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-4-(5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2- methylpiperazine-1-carboxylate (500 mg, 0.83 mmol, prepared following the procedures of the first two steps of compound 192 synthesis) in dioxane (10 mL) were added 4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.48 mL, 3.3 mmol), TEA (0.58 mL, 4.1 mmol), X-Phos (40 mg, 0.084 mmol) and Pd2(dba)3(77 mg, 0.084 mmol). The resulting mixture was stirred at 95oC overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude tert-butyl (R)-2-methyl-4-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1- carboxylate as a brown oil, which was used in the next step directly. LC / MS ESI (m / z): 598 (M+H)+. Step 2. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (500 mg, 0.83 mmol) in dioxane (10 mL) and H2O (2 mL) were added 2-bromopyridine (0.16 mL, 1.6 mmol), K2CO3(580 mg, 4.1 mmol) and Pd(dppf)Cl2(61 mg, 0.084 mmol). The resulting mixture was heated at 90oC overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography (silica gel, 0~50%, ethyl acetate in petroleum ether) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (410 mg, 89%) as a yellow solid. LC / MS ESI (m / z): 549 (M+H)+. Step 3. tert-Butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)piperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (410 mg, 0.74 mmol) in THF (5 mL) was added TBAF (4.5 mL, 1.0M in THF). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, methanol in dichloromethane) to afford tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (240 mg, 81%) as a yellow solid. LC / MS ESI (m / z): 395 (M+H)+. Step 4. tert-Butyl (R)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-2-methyl-4-(5-(pyridin-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 0.35 mmol) in DMF (5 mL) were added 1,3-difluoro-5-iodobenzene (100 mg, 0.42 mmol), trans-cyclohexane-1,2-diamine (12 mg, 0.11 mmol), CuI (20 mg, 0.11 mmol) and K3PO4(230 mg, 1.1 mmol). The resulting mixture was heated at 120oC overnight. After cooling to room temperature, the reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to give crude product which was further purified by prep-HPLC to afford tert-butyl (R)-4-(7-(3,5-difluorophenyl)- 5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (110 mg, 61%) as a white solid. LC / MS ESI (m / z): 507 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.72 – 8.67 (m, 1H), 8.52 (s, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.31 – 7.26 (m, 1H), 6.82 (tt, J = 8.8, 2.3 Hz, 1H), 4.30 – 4.15 (m, 1H), 3.90 – 3.74 (m, 2H), 3.62 – 3.46 (m, 1H), 3.08 (dd, J = 13.3, 3.9 Hz, 1H), 2.94 – 2.72 (m, 2H), 1.44 (s, 9H), 1.10 (d, J = 6.8 Hz, 3H). The following compounds were prepared by procedures analogous to the synthesis of compound 215 using the corresponding aryl halides in steps 2 and 4.

[0014] Example 49. Synthesis of tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (Compound 232) Compound 232To a solution of tert-butyl (2R,5S)-4-[7-(3,5-difluorophenyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylate (150 mg, 0.26 mmol, prepared following an analogous procedure described for compound 242) in toluene (5 mL) were added cyclopropylboronic acid (45 mg, 0.52 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (17 mg, 0.030 mmol) and K2CO3(730 mg, 5.3 mmol). The resulting mixture was heated to 80℃ overnight. After cooling to room temperature, solvent was removed and the residue was purified by flash column chromatography to afford tert-butyl (2R,5S)-4-(5-cyclopropyl-7-(3,5-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,5- dimethylpiperazine-1-carboxylate (90 mg, 71%) as a solid. LC / MS ESI (m / z): 484 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.36 (dd, J = 8.3, 2.2 Hz, 2H), 6.93 (d, J = 0.8 Hz, 1H), 6.76 (tt, J = 8.8, 2.3 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.41 (s, 1H), 3.77 (m, 3H), 3.58 (d, J = 11.0 Hz, 1H), 2.05 – 1.97 (m, 1H), 1.50 (s, 9H), 1.17 (t, J = 6.8 Hz, 6H), 1.06 – 1.01 (m, 2H), 0.89 – 0.82 (m, 1H), 0.66 (dd, J = 8.7, 4.3 Hz, 1H). Example 50. Synthesis of tert-butyl-(S)-4-(7-(3,5-difluorophenyl)-5-(pyridin-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Compound 235) Compound 235Step 1. tert-Butyl-(S)-3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate A suspension of tert-butyl-(3S)-4-[5-iodo-7-(4-methylbenzenesulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylate (1.8 g, 3.0 mmol, prepared following the procedure described for compound 268), 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.3 mL, 9.0 mmol), Et3N (1.6 mL, 12 mmol), X-Phos (0.43 g, 0.90 mmol) and Pd2(dba)3(0.83 g, 0.90 mmol) in dioxane (30 mL) was stirred at 95℃ under a N2atmosphere for 18h. The mixture was cooled to room temperature and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was used in the next step directly. LC / MS (ESI) (m / z): 598 (M+H)+ Step 2. tert-Butyl-(S)-3-methyl-4-(5-(pyridin-2-yl)-7-tosyl-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-1-carboxylate A suspension of tert-butyl-(3S)-3-methyl-4-[7-(4-methylbenzenesulfonyl)-5- (tetramethy...

Claims

CLAIMS What is claimed is:

1. A compound of formula (Ia)or a pharmaceutically acceptable salt thereof, wherein R1is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl, optionally substituted by 1-5 independently selected R8; R3iseach of R4and R6is independently selected from the group consisting of H, hydroxy, halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkylthio, and NRaRb; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; or when R1or R2is cycloalkyl or heterocycloalkyl, two R7or two R8on the same carbon can be taken together to form oxo, or any two R7or two R8can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridgeof 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1- 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond, wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,–(CH2)0-2-C3-7 cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; m is 1 or 2; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, 6, 7, or 8; wherein m + n is 2, 3, or 4; and R1and R2are not both aryl.

2. The compound of claim 1 of formula (Ia)or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl optionally substituted by 1-5 independently selected R8; R3iseach of R4and R6is H; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl, and NRaRb, wherein each C1-6alkyl and C1-6alkoxy are optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, and C1-6alkoxy, and each C3-7cycloalkyl is optionally substituted with substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy and C1-6alkyl; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy; each R10is selected independently from the group consisting of C1-6alkyl and C1-6haloalkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, hydroxyl, and C1-6alkoxy; or two R10on the same carbon can be taken together to form oxo; or any two R10can be taken together with the atoms to which they are attached to form an edge fused or spiro fused ring of 3-7 members, or a bridge of 1 to 3 carbons or a single bond,wherein the ring or bridge is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6haloalkyl, and C1-6alkyl; each Raand Rbis independently selected from H, C1-6alkyl, C(O)-O-C1-6alkyl, C(O)-O-C2-6alkenyl,–(CH2)0-2-C3-7cycloalkyl, and 3-7 membered heterocycloalkyl, wherein each alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 substituents selected from halogen and C1-6alkoxy; or Raand Rbcan be taken together with the nitrogen to which they are attached to form a 4-7 membered ring; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

3. The compound of claim 1 of formula (Ia)or a pharmaceutically acceptable salt thereof, wherein R1is pyridyl optionally substituted by 1-5 independently selected R7; R2is C1-6alkyl optionally substituted by 1-5 independently selected R8; R3iseach of R4and R6is H; each of R7and R8are independently selected at each occurrence from the group consisting of deuterium, hydroxy, halogen, cyano, C1-6alkyl, and C1-6alkoxy; R9is C1-6alkyl, optionally substituted with substituents independently selected from the group consisting of deuterium, halogen, hydroxyl, and C1-6alkoxy;each R10is selected independently from the group consisting of C1-6alkyl, and C1-6haloalkyl, each optionally substituted with 1-5 deuterium; and p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

4. The compound of claim 1, wherein R1is aryl optionally substituted by 1-5 independently selected R7;.

5. The compound of claim 4, wherein R1is phenyl optionally substituted with 1-3 independently selected R7.

6. The compound of claim 4 or 5, wherein each R7is independently selected from H, halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, or C1-6haloalkoxy.

7. The compound of claim 1, wherein R1is heteroaryl, cycloalkyl, or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7.

8. The compound of any one of claims 1 or 7, wherein R1is heteroaryl or heterocycloalkyl, each R1optionally substituted by 1-5 independently selected R7.

9. The compound of any one of claims 1 or 7-8, wherein R1is heteroaryl optionally substituted by 1-5 independently selected R7.

10. The compound of claim 2 or 9, wherein R1is monocyclic heteroaryl optionally substituted by 1-5 independently selected R7.

11. The compound of claim 10, wherein R1is monocyclic heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring atoms selected independently from N, O, and S, wherein R1is optionally substituted by 1-4 independently selected R7.

12. The compound of claim 10, wherein R1is monocyclic nitrogen-containing heteroaryl of 5-6 ring atoms with 1, 2 or 3 ring heteroatoms selected from N only, wherein R1is optionally substituted by 1-4 independently selected R7.

13. The compound of claim 12, wherein R1is pyridine, pyrimidine, pyrazine, pyridazine, thiazole, oxazole, pyrrole, imidazole, or pyrazole, optionally substituted by 1-4 independently selected R7.

14. The compound of claim 13, wherein R1is pyridine, thiazole, or pyrazole, optionally substituted by 1-4 independently selected R7.

15. The compound of claim 14, wherein R1is pyridine, optionally substituted by 1-4 independently selected R7.

16. The compound of claim 15, wherein R1is 2-pyridyl, optionally substituted by 1-4 independently selected R7.

17. The compound of claim 15, wherein R1is ,18. The compound of claim 17, wherein R1is tituted by 1-4 independently selected R7.

20. The compound of claim 7, wherein R1is heterocycloalkyl of 4-8 ring atoms, wherein 1-3 ring atoms are selected from N, O, and S, and R1is optionally substituted by 1-4 independently selected R7.

21. The compound of claim 20, wherein R1is tetrahydropyran, azetidine, pyrrolidine, morpholine, or piperidine, and R1is optionally substituted by 1-4 independently selected R7.

22. The compound of claim 7, wherein R1is C3-7cycloalkyl, optionally substituted by 1-4 independently selected R7.

23. The compound of claim 22, wherein R1is a cyclohexyl with an optional one or two carbon bridged ring, and R1is optionally substituted by 1-4 independently selected R7.

24. The compound of any one of claims 1-23 wherein each R8is independently selected from deuterium, hydroxy, halogen, cyano, or C1-6alkoxy.

25. The compound of any one of claims 1-24, wherein R2is C1-6alkyl optionally substituted by 1-5 independently selected halogens.

26. The compound of claim 25, wherein R2is Me, Et, CHF2, or CF3.

27. The compound of any one of claims 1-25, wherein R2is not substituted.

28. The compound of any one of claims 1-27, wherein m is 1 and n is 1.

29. The compound of any one of claims 1-28, wherein p is 0, 1, 2, 3, 4, 5, or 6.

30. The compound of claim 29, wherein each R10is independently selected from the group consisting of C1-6alkyl and C1-6haloalkyl, each optionally substituted with 1-5 deuteriums.

31. The compound of claim 30, wherein each R10is methyl.

32. The compound of claim 30 or 31, wherein p is 1, 2, 3, 4, 5, or 6.

33. The compound of claim 32, wherein R3is substituted with an edge fused or spiro fused cyclopropane; or R3includes a one or two carbon bridge or a single bond bridge; and R3is optionally additionally substituted by 1-4 R10.

34. The compound of claim 33, wherein R3is35. The compound of claim 32, wherein R3is36. The compound of claim 35, wherein R3is37. The compound of any one of claims 1-35, wherein R3is not substituted by any additional R10.

38. The compound of any one of claims 1-37, wherein R4is H.

39. The compound of any one of claims 1-38, wherein R6is H.

40. The compound of any one of claims 1-39, wherein R4and R6are H.

41. The compound of any one of claims 1-40, wherein each of R7and R8are independently selected at each occurrence from the group consisting of hydroxy, halogen, cyano, C1-6alkyl, C1-6alkoxy, and C3-7cycloalkyl, wherein each C1-6alkyl and C1-6alkoxy is optionally substituted with 1-3 halogens.

42. The compound of any one of claims 1-63, wherein each R7is independently selected at each occurrence from the group consisting of halogen, cyano, C1-6alkyl, C1-6alkoxy, and CF3.

43. The compound of any one of claims 1-42, wherein R9is C1-6alkyl; optionally substituted with 1-5 halogens or 1-9 deuteriums.

44. The compound of claim 43, wherein R9is ethyl, isopropyl, or t-butyl; each optionally substituted with 1-5 halogens or 1-9 deuteriums.

45. The compound of claim 44, wherein R9is ethyl, isopropyl, or t-butyl.

46. The compound of claim 44, wherein R9is -C(CD3)3, -CH(CD3)2, or -CD2CD3.

47. The compound of claim 43, wherein R9is Me, Et, t-butyl, -C(CD3)3, -CH(CD3)2, -wherein the variable definitions are as described in the specification and claims.

49. A compound of formula (Ic)wherein the variable definitions are as described in the specification and claims.

50. A compound of Formula (I), or any subformula thereof, selected from the compounds disclosed in the specification, or a pharmaceutically acceptable salt thereof.

51. A compound of any one of claims 1-50, wherein the compound achieves at least 50% of the maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for TRPML1, and has an EC50less than 1 µM.

52. A compound of any one of claims 1-51, wherein the compound achieves a maximal current obtained with 30 µM ML-SA1 in a patch clamp assay for TRPML1 which is at least 10 fold the maximal current achieved for any other TRPML.

53. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-52.

54. A method of modulating TRPML ion channels, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 53 or a compound of any one of claims 1-52.

55. A method of treating a disease or disorder which can be treated by modulation of TRPML ion channels, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 53 or a compound of any one of claims 1-52.

56. A method of treating a disorder which can be treated by modulation of lysosomes, the method comprising administering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition of claim 53 or a compound of any one of claims 1- 52.

57. A method of treating a disorder selected from the group consisting of a ciliopathy, neurodegenerative disease, lysosomal storage disorder, lysosomal transport disorder, glycogen storage disorder, cholesteryl ester storage disease, a muscular disease (e.g., muscular dystrophy), a disease related to aging (e.g., photo aging of the skin), macular degeneration (e.g., Stargardt’s or age related), and cancer (e.g., cancers of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testes, colon, pancreas, or skin), the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 53 or a compound of any one of claims 1-52.

58. The method of claim 57, wherein the disorder is a ciliopathy.

59. The method of claim 58, wherein the ciliopathy is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephronophthisis, Joubert Syndrome, Mecke-Gruber Syndrome, oral-facial-digital syndrome, Senior Loken Syndrome, Birt-Hogg-Dube syndrome, Leber’s congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia.

60. The method of claim 59, wherein the disorder is polycystic kidney disease 61. The method of claim 60, wherein the disorder is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease.

62. The method of claim 61, wherein the disorder is autosomal dominant polycystic kidney disease.

63. The method of claim 57, wherein the disorder is a neurodegenerative disorder.

64. The method of claim 63, wherein the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, GBA-Parkinson’s disease, LRRK2 Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease,progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewy body dementia, Pick’s disease, and multi system atrophy.

65. The method of claim 57, wherein the disorder is a lysosomal storage disorder.

66. The method of claim 65, wherein the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, neuronopathic Gaucher’s disease, sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, gangliosidoses, Gaucher Disease, Lysosomal acid lipase deficiency, sulfatidoses, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses.

67. The method of claim 66, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, Galactosialidosis, Fabry disease, Schindler disease, beta-galactosidase disorder, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay- Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, Saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie sundrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I-cell disease, pseudo-Hurler polydystrophy, phosphotransferease deficiency, mucolipidin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipfuscinosis, late infantile variant neuronal ceroid lipfuscinosis, type 7 neuronal ceroid lipfuscinosis, northern epilepsy neuronal ceroid lipfuscinosis, Turkish late infantile neuronal ceroid lipfuscinosis, German / Serbian late infantile neuronal ceroid lipfuscinosis, congential cathepsin D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, aspartylgluosaminuria, and fucosidosis.

68. The method of claim 67, wherein the lysosomal storage disorder is selected from the group consisting of Niemann-Pick disease, Gaucher’s disease, and neuronopathic Gaucher’s disease.

69. The method of claim 67, wherein the disorder is a lysosomal transport disease selected from the group consisting of cystinosis, pycnodysostosis, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease.

70. The method of claim 67, wherein the disorder is a glycogen storage disease selected from the group consisting of Pompe disease and Danon disease.

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